Updated on 2025/10/23

写真a

 
IDA Hiroko
 
Organization
Academic Assembly Institute of Medicine and Dentistry SHIGAKU KEIRETU Associate Professor
Faculty of Dentistry Department of Dentistry Associate Professor
Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction Associate Professor
Title
Associate Professor
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Degree

  • 博士（歯学） ( 2000.3   新潟大学 )

Research Areas

  • Life Science / Oral pathobiological science

  • Life Science / Oral biological science

Research History (researchmap)

  • Niigata University   Faculty of Dentistry School of Dentistry   Associate Professor

    2008.9

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  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction   Associate Professor

    2008.9

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  • Niigata University   University Medical and Dental Hospital Surgical Care   Lecturer

    2007.9 - 2008.8

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  • Niigata University Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction   Associate Professor

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Research History

  • Niigata University   Faculty of Dentistry School of Dentistry   Associate Professor

    2008.9

  • Niigata University   Graduate School of Medical and Dental Sciences Oral Life Science Tissue Regeneration and Reconstruction   Associate Professor

    2008.9

  • Niigata University   University Medical and Dental Hospital Surgical Care   Lecturer

    2007.9 - 2008.8

Professional Memberships

Committee Memberships

  • 日本解剖学会   Anatomical Science International. Managing Editor  

    2021.4   

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  • 日本解剖学会   ダイバーシティ推進委員会  

    2017.4 - 2023.3   

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Papers

  • Role of glucose metabolism in amelogenesis. Reviewed International journal

    Hiroko Ida-Yonemochi

    Journal of oral biosciences   67 ( 2 )   100667 - 100667   2025.6

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND: Cell energy metabolism plays a pivotal role in organ development and function by regulating cell behavior in pathophysiological conditions. Glucose metabolism is the central cascade for obtaining energy in mammalian cells, and cells alter the glucose metabolic pathway depending on intra- and extracellular environments. Therefore, glucose metabolism is closely associated with cell differentiation stages, and cell energy metabolism plays a vital role not only in energy production but also in cell fate regulation in organogenesis. HIGHLIGHT: During enamel formation, the timing of the expression of passive and active glucose transporters, glycogen synthesis, and glycogen degradation is strictly regulated according to the energy demand of ameloblast-lineage cells. These glucose metabolic reactions are particularly active in the maturation stage of ameloblasts. Furthermore, autophagy, a key regulator of cellular energy homeostasis that modulates glucose metabolism, occurs during both the secretory and maturation stages of ameloblasts. Disruption of glucose metabolism cascade and autophagy induces enamel hypoplasia, as demonstrated in both in vitro and in vivo models. CONCLUSION: Adequate energy supply via glucose metabolism is essential for enamel matrix secretion and maturation. A thorough understanding of the precise regulation of energy metabolism in amelogenesis facilitates comprehension of the normal enamel formation process and pathological conditions affecting it. This review summarizes glucose metabolic processes during amelogenesis, focusing on glucose uptake, glycogenesis, and glycogenolysis.

    DOI： 10.1016/j.job.2025.100667

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  • The potential role of chromodomain helicase DNA-binding protein 3 in defining the cervical width by regulating the early growth stage of the apical papilla during tooth development. Reviewed International journal

    Kento Shimamura, Toshiki Nojiri, Hisatomo Kondo, Yunosuke Ikeda, Rika Yasuhara, Hiroko Ida-Yonemochi, Keishi Otsu, Hidemitsu Harada, Kenji Mishima, Hayato Ohshima, Takuya Kobayashi, Tarou Irié

    Journal of oral biosciences   100604 - 100604   2024.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    OBJECTIVE: This study aimed to evaluate the role of the chromodomain helicase DNA-binding protein 3 (CHD3) in tooth morphogenesis in Chd3 knockout mice. METHODS: Chd3 knockout mice were generated using the CRISPR-Cas9 method. Mandibular first molars were extracted from the mice and their littermates and morphometrically analyzed. Subsequent histological and immunohistochemical analyses of teeth were performed at each developmental stage. Chd3 knockdown in mesenchymal cells from the dental papilla (mDP) and Hertwig's epithelial root sheath (HERS) was performed by Chd3 shRNA transduction or a control using an adenoviral vector. These effects were examined using cell proliferation assays and quantitative real-time polymerase chain reaction. RESULTS: Narrowing of tooth cervical width was observed in mandibular first molars of Chd3 knockout mice. On postnatal day (PN) 8, the cervical width was narrow before root formation in tooth germs. The number of Ki-67-positive cells decreased in the dental mesenchyme at PN1 and apical papilla at PN8. Chd3 promoted the proliferation of dental mesenchymal cells, but no significant changes were observed in HERS epithelial cells. Chd3 maintained sonic hedgehog (Shh) expression and inhibited that of bone morphogenetic protein (Bmp)4 in dental mesenchymal cells, maintaining Shh and Wnt3a expression and inhibited that of Bmp2 in HERS epithelial cells. CONCLUSION: Chd3 may regulate tooth cervical width during the early growth stage of the apical papilla via Shh, Bmp, and Wnt signaling.

    DOI： 10.1016/j.job.2024.100604

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  • PLAG1 overexpression in salivary gland duct-acinar units results in epithelial tumors with acinar-like features: Tumorization of luminal stem/progenitor cells may result in the developmen t of salivary gland tumors consisting of only luminal cells Reviewed

    Yunosuke Ikeda, Rika Yasuhara, Junichi Tanaka, Hiroko Ida-Yonemochi, Haruhiko Akiyama, Keishi Otsu, Ikuya Miyamoto, Hidemitsu Harada, Hiroyuki Yamada, Toshiyuki Fukada, Tarou Irié

    Journal of Oral Biosciences   2024.8

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.job.2024.08.002

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  • Loss of autophagy disrupts stemness of ameloblast-lineage cells in aging Reviewed International journal

    Hiroko Ida-Yonemochi, Keishi Otsu, Tarou Irié, Atsushi Ohazama, Hidemitsu Harada, Hayato Ohshima

    Journal of Dental Research   in press   220345231209931 - 220345231209931   2024

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Autophagy is one of the intracellular degradation pathways and maintains cellular homeostasis, regulating the stress response, cell proliferation, and signal transduction. To elucidate the role of autophagy in the maintenance of dental epithelial stem cells and the subsequent enamel formation, we analyzed autophagy-deficient mice in epithelial cells (Atg7f/f;KRT14-Cre mice), focusing on the influence of aging and stress environments. We also performed in vitro cell and organ culture experiments with an autophagy inhibitor. In young Atg7f/f;KRT14-Cre mice, morphological change was not obvious in maxillary incisors, except for the remarkable cell death in the stratum intermedium of the transitional stage. However, under stress conditions of hyperglycemia, the incisor color changed to white in diabetes Atg7f/f;KRT14-Cre mice. Regarding dental epithelial stem cells, the shape of the apical bud region of the incisor became irregular with age, and odontoma was formed in aged Atg7f/f;KRT14-Cre mice. In addition, the shape of apical bud culture cells of Atg7f/f;KRT14-Cre mice became irregular and enlarged atypically, with epigenetic changes during culture, suggesting that autophagy deficiency may induce tumorigenesis in dental epithelial cells. The epigenetic change and upregulation of p21 expression were induced by autophagy inhibition in vivo and in vitro. These findings suggest that autophagy is important for the regulation of stem cell maintenance, proliferation, and differentiation of ameloblast-lineage cells, and an autophagy disorder may induce tumorigenesis in odontogenic epithelial cells.

    DOI： 10.1177/00220345231209931

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  • Establishing protein expression profiles involved in tooth development using a proteomic approach. Reviewed

    Junko Shimomura-Kuroki, Masayuki Tsuneki, Hiroko Ida-Yonemochi, Yuta Seino, Keiko Yamamoto, Yoshitoshi Hirao, Tadashi Yamamoto, Hayato Ohshima

    Odontology   2023.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    Various growth and transcription factors are involved in tooth development and developmental abnormalities; however, the protein dynamics do not always match the mRNA expression level. Using a proteomic approach, this study comprehensively analyzed protein expression in epithelial and mesenchymal tissues of the tooth germ during development. First molar tooth germs from embryonic day 14 and 16 Crlj:CD1 (ICR) mouse embryos were collected and separated into epithelial and mesenchymal tissues by laser microdissection. Mass spectrometry of the resulting proteins was carried out, and three types of highly expressed proteins [ATP synthase subunit beta (ATP5B), receptor of activated protein C kinase 1 (RACK1), and calreticulin (CALR)] were selected for immunohistochemical analysis. The expression profiles of these proteins were subsequently evaluated during all stages of amelogenesis using the continuously growing incisors of 3-week-old male ICR mice. Interestingly, these three proteins were specifically expressed depending on the stage of amelogenesis. RACK1 was highly expressed in dental epithelial and mesenchymal tissues during the proliferation and differentiation stages of odontogenesis, except for the pigmentation stage, whereas ATP5B and CALR immunoreactivity was weak in the enamel organ during the early stages, but became intense during the maturation and pigmentation stages, although the timing of the increased protein expression was different between the two. Overall, RACK1 plays an important role in maintaining the cell proliferation and differentiation in the apical end of incisors. In contrast, ATP5B and CALR are involved in the transport of minerals and the removal of organic materials as well as matrix deposition for CALR.

    DOI： 10.1007/s10266-023-00790-4

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  • Role of chondroitin sulfate in the developmental and healing process of the dental pulp in mice. Reviewed International journal

    Hiroko Ida-Yonemochi, Kosei Takeuchi, Hayato Ohshima

    Cell and tissue research   388 ( 1 )   133 - 148   2022.4

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Chondroitin sulfate proteoglycan (CSPG), one of the major extracellular matrices, plays an important part in organogenesis. Its core protein and chondroitin sulfate (CS) chain have a specific biological function. To elucidate the role of CS in the developmental and healing process of the dental pulp, we performed an experimental tooth replantation in CS N-acethylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. We also performed cell proliferation assay and qRT-PCR analysis for the WT and T1KO primary dental pulp cells using T1-siRNA technique and external CS. During tooth development, CS was diffusely expressed in the dental papilla, and with dental pulp maturation, CS disappeared from the differentiated areas, including the odontoblasts. In fully developed molars, CS was restricted to the root apex region colocalizing with Gli1-positive cells. In the healing process after tooth replantation, CD31-positive cells accumulated in the CS-positive stroma in WT molars. In T1KO molars, the appearance of Ki67- and Gli1-positive cells in the dental pulp was significantly fewer than in WT molars in the early healing stage, and collagen I-positive reparative dentin formation was not obvious in T1KO mice. In primary culture experiments, siRNA knockdown of T1 gene significantly suppressed cell proliferation in WT dental pulp cells, and the mRNA expression of cyclin D1 and CD31 was significantly upregulated by external CS in T1KO dental pulp cells. These results suggest that CS is involved in the cell proliferation and functional differentiation of dental pulp constituent cells, including vascular cells, in the healing process of dental pulp tissue after tooth injury.

    DOI： 10.1007/s00441-022-03575-3

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  • Exploration of the role of the subodontoblastic layer in odontoblast-like cell differentiation after tooth drilling using Nestin-enhanced green fluorescent protein transgenic mice. Reviewed International journal

    Chihiro Imai, Hiroto Sano, Angela Quispe-Salcedo, Kotaro Saito, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Hideyuki Okano, Hayato Ohshima

    Journal of oral biosciences   64 ( 1 )   77 - 84   2022.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    OBJECTIVES: Original odontoblasts and regenerated odontoblast-like cells (OBLCs) may differently regulate Nestin expression. This study aimed to investigate the role of the subodontoblastic layer (SOBL) using green fluorescent protein (GFP) reactivity in the process of OBLC differentiation after tooth drilling in Nestin-enhanced GFP transgenic mice. METHODS: A groove-shaped cavity was prepared on the mesial surface of the maxillary first molars of 5- or 6-week-old mice under deep anesthesia. Immunohistochemical staining for Nestin and GFP and Nestin in situ hybridization were conducted on the sections obtained at 1-14 days postoperative. RESULTS: Odontoblasts showed intense endogenous Nestin protein and mRNA expression, whereas the coronal SOBL cells showed a Nestin-GFP-positive reaction in the control groups. The injured odontoblasts had significantly decreased Nestin immunoreactivity as well as decreased expression of Nestin mRNA 1-2 days after the injury; subsequently, newly differentiated OBLCs were arranged along the pulp-dentin border, with significantly increased Nestin expression as well as increased expression of Nestin mRNA on days 3-5 to form reparative dentin. Nestin-GFP-positive cells at the pulp-dentin border significantly increased in number on days 1 and 2. GFP(+)/Nestin(+) and GFP(-)/Nestin(+) cells were intermingled in the newly differentiated OBLCs. CONCLUSIONS: The commitment of Nestin-GFP-positive cells into Nestin-positive OBLCs suggests that the restriction of endogenous Nestin protein and mRNA expression in the static SOBL cells was removed by exogenous stimuli, resulting in their migration along the pulp-dentin border and their differentiation into OBLCs.

    DOI： 10.1016/j.job.2022.01.001

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  • Role of osteopontin in the process of pulpal healing following tooth replantation in mice Reviewed International journal

    Suzuki-Barrera K, Makishi S, Nakatomi M, Saito K, Ida-Yonemochi H, Ohshima H

    Regenerative Therapy   21   460 - 468   2022

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    Language：English   Publishing type：Research paper (scientific journal)  

    INTRODUCTION: The role of osteopontin (OPN) following severe injury remains to be elucidated, especially its relationship with type I collagen (encoded by the Col1a1 gene) secretion by newly-differentiated odontoblast-like cells (OBLCs). In this study, we examined the role of OPN in the process of reparative dentin formation with a focus on reinnervation and revascularization after tooth replantation in Opn knockout (KO) and wild-type (WT) mice. METHODS: Maxillary first molars of 2- and 3-week-old-Opn KO and WT mice (Opn KO 2W, Opn KO 3W, WT 2W, and WT 3W groups) were replanted, followed by fixation 3-56 days after operation. Following micro-computed tomography analysis, the decalcified samples were processed for immunohistochemistry for Ki67, Nestin, PGP 9.5, and CD31 and in situ hybridization for Col1a1. RESULTS: An intense inflammatory reaction occurred to disrupt pulpal healing in the replanted teeth of the Opn KO 3W group, whereas dental pulp achieved healing in the Opn KO 2W and WT groups. The tertiary dentin in the Opn KO 3W group was significantly decreased in area compared with the Opn KO 2W and WT groups, with a significantly low percentage of Nestin-positive, newly-differentiated OBLCs during postoperative days 7-14. In the Opn KO 3W group, the blood vessels were significantly decreased in area and pulp healing was disturbed with a failure of pulpal revascularization and reinnervation. CONCLUSIONS: OPN is necessary for proper reinnervation and revascularization to deposit reparative dentin following severe injury within the dental pulp of erupted teeth with advanced root development.

    DOI： 10.1016/j.reth.2022.09.011

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  • The Sonic Hedgehog–Patched–Gli Signaling Pathway Maintains Dental Epithelial and Pulp Stem/Progenitor Cells and Regulates the Function of Odontoblasts Reviewed

    Yuko Ishikawa, Hiroko Ida-Yonemochi, Kotaro Saito, Mitsushiro Nakatomi, Hayato Ohshima

    Frontiers in Dental Medicine   2   2021.4

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    Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    This study aimed to elucidate the role of the Sonic hedgehog (Shh)–Patched (Ptch)–Gli signaling pathway in maintaining dental epithelial and pulp stem/progenitor cells and regulating the function of odontoblasts. Doxycycline (dox)-inducible histone 2B (H2B)–green fluorescent protein (GFP) transgenic mice ingested dox at prenatal embryonic days 14.5 or 15.5 and their offspring were collected from postnatal day 1 (P1) to week 3 (P3W). Immunohistochemistry for Gli1, Ptch1, and Ptch2 and<italic>in situ</italic>hybridization for<italic>Shh</italic>and<italic>Ptch1</italic>were conducted. Mandibular incisors of postnatal day 2 H2B-GFP transgenic and wild-type mice were cultivated in a nutrient medium with Shh antibody for 4 days and subsequently processed for immunohistochemistry for Sox2. In molars, dense H2B-GFP-label-retaining cells (H2B-GFP-LRCs) were densely distributed throughout the dental pulp during P1 to postnatal week 2 (P2W) and decreased in number by postnatal P3W, whereas the number of dense H2B-GFP-LRCs in the subodontoblastic layer increased in number at P2W. Gli1<sup>+</sup>and Pthc1<sup>+</sup>cells were distributed throughout the enamel organ and dental pulp, including the odontoblast and subodontoblastic layers.<italic>Shh</italic>mRNA was expressed in the inner enamel epithelium and shifted into odontoblasts after dentin deposition.<italic>Ptch1</italic>mRNA was expressed in the inner enamel epithelium and cuspal pulpal tissue on P1 and decreased in intensity from postnatal week 1 to P3W. In incisors, the apical bud contained H2B-GFP-LRCs, Gli1<sup>+</sup>cells, and Ptch1<sup>+</sup>cells. The addition of Shh antibody to explants induced a decrease in the number of Sox2<sup>+</sup>cells due to the increase in apoptotic cells in the apical bud. Thus, the Shh–Ptch–Gli signaling pathway plays a role in maintaining quiescent adult stem cells and regulating the function of odontoblasts.

    DOI： 10.3389/fdmed.2021.651334

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  • Oxygen regulates epithelial stem cell proliferation via RhoA-actomyosin-YAP/TAZ signal in mouse incisor. Reviewed International journal

    Keishi Otsu, Hiroko Ida-Yonemochi, Shojiro Ikezaki, Masatsugu Ema, Jiro Hitomi, Hayato Ohshima, Hidemitsu Harada

    Development (Cambridge, England)   148 ( 4 )   2021.2

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    Stem cells are maintained in specific niches that strictly regulate their proliferation and differentiation for proper tissue regeneration and renewal. Molecular oxygen (O2) is an important component of the niche microenvironment, but little is known about how O2 governs epithelial stem cell (ESC) behavior. Here, we demonstrate that O2 plays a crucial role in regulating the proliferation of ESCs using the continuously growing mouse incisors. We have revealed that slow-cycling cells in the niche are maintained under relatively hypoxic conditions compared with actively proliferating cells, based on the blood vessel distribution and metabolic status. Mechanistically, we have demonstrated that, during hypoxia, HIF1α upregulation activates the RhoA signal, thereby promoting cortical actomyosin and stabilizing the adherens junction complex, including merlin. This leads to the cytoplasmic retention of YAP/TAZ to attenuate cell proliferation. These results shed light on the biological significance of blood-vessel geometry and the signaling mechanism through microenvironmental O2 to orchestrate ESC behavior, providing a novel molecular basis for the microenvironmental O2-mediated stem cell regulation during tissue development and renewal.

    DOI： 10.1242/dev.194787

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  • Hypoxia-Responsive Oxygen Nanobubbles for Tissues-Targeted Delivery in Developing Tooth Germs. Reviewed International journal

    Eun-Jung Kim, Ji-Eun Lee, Semi Yoon, Dong-Joon Lee, Han Ngoc Mai, Hiroko Ida-Yonemochi, Jonghoon Choi, Han-Sung Jung

    Frontiers in cell and developmental biology   9   626224 - 626224   2021

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    Hypoxia is a state of inadequate supply of oxygen. Increasing evidence indicates that a hypoxic environment is strongly associated with abnormal organ development. Oxygen nanobubbles (ONBs) are newly developed nanomaterials that can deliver oxygen to developing tissues, including hypoxic cells. However, the mechanisms through which nanobubbles recover hypoxic tissues, such as developing tooth germs remain to be identified. In this study, tooth germs were cultured in various conditions: CO2 chamber, hypoxic chamber, and with 20% ONBs for 3 h. The target stages were at the cap stage (all soft tissue) and bell stage (hard tissue starts to form). Hypoxic tooth germs were recovered with 20% ONBs in the media, similar to the tooth germs incubated in a CO2 chamber (normoxic condition). The tooth germs under hypoxic conditions underwent apoptosis both at the cap and bell stages, and ONBs rescued the damaged tooth germs in both the cap and bell stages. Using kidney transplantation for hard tissue formation in vivo, amelogenesis and dentinogenesis imperfecta in hypoxic conditions at the bell stage were rescued with ONBs. Furthermore, glucose uptake by tooth germs was highly upregulated under hypoxic conditions, and was restored with ONBs to normoxia levels. Our findings indicate that the strategies to make use of ONBs for efficient oxygen targeted delivery can restore cellular processes, such as cell proliferation and apoptosis, glucose uptake, and hypomineralization in hypoxic environments.

    DOI： 10.3389/fcell.2021.626224

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  • Responses of oral-microflora-exposed dental pulp to capping with a triple antibiotic paste or calcium hydroxide cement in mouse molars. Reviewed International journal

    Angela Quispe-Salcedo, Takuichi Sato, Junko Matsuyama, Hiroko Ida-Yonemochi, Hayato Ohshima

    Regenerative therapy   15   216 - 225   2020.12

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    Introduction: Responses of oral-microflora-exposed dental pulp to a triple antibiotic paste (TAP), a mixture of ciprofloxacin, metronidazole, and minocycline in ointment with macrogol and propylene glycol, remain to be fully clarified at the cellular level. This study aimed to elucidate responses of oral-microflora-exposed dental pulp to capping with TAP in mouse molars. Methods: A cavity was prepared on the first molars of 6-week-old mice to expose the dental pulp for 24 h. The exposed pulp was capped with TAP (TAP group) or calcium hydroxide cement (CH group), in addition to the combination of macrogol (M) and propylene glycol (P) (MP, control group), followed by a glass ionomer cement filling. The samples were collected at intervals of 1, 2, and 3 weeks, and immunohistochemistry for nestin and Ki-67 and deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL) assay were performed in addition to quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Results: The highest occurrence rate of pulp necrosis was found in the control group followed by the CH group at Weeks 2 and 3, whereas the highest occurrence rate of healed areas in the dental pulp was observed in the TAP group at each time point. Tertiary dentin formation was first observed in the dental pulp of the TAP group at Week 2. In contrast, bone-like and/or fibrous tissues were frequently observed in the CH group. qRT-PCR analyses clarified that TAP activated the stem and dendritic cells at Weeks 1 and 2, respectively. Conclusions: The use of TAP as a pulp-capping agent improved the healing process of oral-microflora-exposed dental pulp in mouse molars.

    DOI： 10.1016/j.reth.2020.10.001

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  • Functional Expression of Sodium-Dependent Glucose Transporter in Amelogenesis. Reviewed International journal

    H Ida-Yonemochi, K Otsu, H Harada, H Ohshima

    Journal of dental research   99 ( 8 )   977 - 986   2020.7

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Glucose is an essential source of energy for mammalian cells and is transported into the cells by glucose transporters. There are 2 types of glucose transporters: one is a passive glucose transporter, GLUT (SLC2A), and the other is a sodium-dependent active glucose transporter, SGLT (SLC5A). We previously reported that the expression of GLUTs during tooth development is precisely and spatiotemporally controlled and that the glucose uptake mediated by GLUT1 plays a crucial role in early tooth morphogenesis and tooth size determination. This study aimed to clarify the localization and roles of SGLT1 and SGLT2 in murine ameloblast differentiation by using immunohistochemistry, immunoelectron microscopy, an in vitro tooth organ culture experiment, and in vivo administration of an inhibitor of SGLT1/2, phloridzin. SGLT1, which has high affinity with glucose, was immunolocalized in the early secretory ameloblasts and the ruffle-ended ameloblasts in the maturation stage. However, SGLT2, which has high glucose transport capacity, was observed in the stratum intermedium, papillary layer, and ameloblasts at the maturation stage and colocalized with Na+-K+-ATPase. The inhibition of SGLT1/2 by phloridzin in the tooth germs induced the disturbance of ameloblast differentiation and enamel matrix formation both in vitro (organ culture) and in vivo (mouse model). The expression of SGLT1 and SGLT2 was significantly upregulated in hypoxic conditions in the ameloblast-lineage cells. These findings suggest that the active glucose uptake mediated by SGLT1 and SGLT2 is strictly regulated and dependent on the intra- and extracellular microenvironments during tooth morphogenesis and that the appropriate passive and active glucose transport is an essential event in amelogenesis.

    DOI： 10.1177/0022034520916130

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  • Reduced enamel epithelium-derived cell niche in the junctional epithelium is maintained for a long time in mice. Reviewed International journal

    Miki Soda, Kotaro Saito, Hiroko Ida-Yonemochi, Kuniko Nakakura-Ohshima, Shinichi Kenmotsu, Hayato Ohshima

    Journal of periodontology   91 ( 6 )   819 - 827   2020.6

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    BACKGROUND: Although numerous reports have demonstrated that the junctional epithelium (JE) is derived from the reduced enamel epithelium (REE), the fate of the REE-derived JE remains controversial. The present study elucidated the fate of the REE-derived JE and the cell dynamics of stem/progenitor cells in the JE following tooth eruption. METHODS: Mandibular first molar germs (embryonic days 15 to postnatal 1-day-old) were transplanted into the socket of 2-week-old mice after extraction of the upper first molars of B6 wild-type (WT) and green fluorescent protein (GFP) transgenic mice. After analysis by µ-CT, paraffin sections were processed for immunohistochemistry for Nestin, Ki67 and GFP. We also performed chasing analysis using BrdU-administered TetOP-H2B-GFP mice. RESULTS: Amelogenesis progressed normally in the cervical areas, and the structure of the JE was like that in normal tooth development. The JE was GFP-negative in transplantations using GFP transgenic mice as the host, and the oral epithelium (OE) showed a positive reaction. By contrast, the JE remained GFP-positive throughout the experimental period in transplantations using GFP transgenic mice as the donor. Chasing analysis revealed that H2B-GFP- and 5-Bromo-2'-deoxyuridine (BrdU)-labeled cells in the basal side of the JE translocated to oral side of the JE as the chasing time increased. Some label-retaining cells remained at the supra-basal cell layer in the JE. CONCLUSION: These results suggest that REE-derived cell niche in the JE is maintained for a long time following tooth eruption. Therefore, the JE may be available as the source of the odontogenic epithelium.

    DOI： 10.1002/JPER.19-0269

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  • Loss of autophagy in chondrocytes causes severe growth retardation. Reviewed International journal

    Yoji Horigome, Hiroko Ida-Yonemochi, Satoshi Waguri, Shunichi Shibata, Naoto Endo, Masaaki Komatsu

    Autophagy   16 ( 3 )   501 - 511   2020.3

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    Chondrogenesis is accompanied by not only cellular renovation, but also metabolic stress. Therefore, macroautophagy/autophagy is postulated to be involved in this process. Previous reports have shown that suppression of autophagy during chondrogenesis causes mild growth retardation. However, the role of autophagy in chondrocyte differentiation still largely remains unclear. Here, we show the important role of autophagy on chondrogenesis. The transition of mesenchymal cells to chondrocytes was severely impaired by ablation of Atg7, a gene essential for autophagy. Mice lacking Atg7 after the transition exhibited phenotypes severer than mutant mice in which Atg7 was removed before the transition. Atg7-deficient chondrocytes accumulated large numbers of glycogen granules, hardly proliferate and died specifically in the proliferative zone without any ER-stress signal. Our results suggest that the suppression of autophagy in prechondrogenic cells drives compensatory mechanism(s) that mitigate defective chondrogenesis, and that autophagy participates in glycogenolysis to supply glucose in avascular growth plates.Abbreviations: DDIT3/CHOP: DNA damage inducible transcript 3; ER: endoplasmic reticulum; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; SQSTM1/p62: sequestosome 1; STBD1: starch-binding domain-containing protein 1.

    DOI： 10.1080/15548627.2019.1628541

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  • Extracellular enzymatically synthesized glycogen promotes osteogenesis by activating osteoblast differentiation via Akt/GSK-3β signaling pathway. Reviewed International journal

    Hiroko Ida-Yonemochi, Eizo Nakagawa, Hiroki Takata, Takashi Furuyashiki, Ryo Kakutani, Mikako Tanaka, Hayato Ohshima

    Journal of cellular physiology   234 ( 8 )   13602 - 13616   2019.8

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Glycogen is the stored form of glucose and plays a major role in energy metabolism. Recently, it has become clear that enzymatically synthesized glycogen (ESG) has biological functions, such as the macrophage-stimulating activity. This study aimed to evaluate the effect of ESG on osteogenesis. MC3T3-E1 cells were cultured with ESG, and their cell proliferative activity and osteoblast differentiation were measured. An in vivo study was conducted in which ESG pellets with BMP-2 were grafted into mouse calvarial defects and histomorphometrically analyzed for the new bone formation. To confirm the effect of ESG on bone growth in vivo, ESG was orally administered to pregnant mice and the femurs of their pups were examined. We observed that ESG stimulated cell proliferation and enhanced messenger RNA expression of osteocalcin and osteopontin in MC3T3-E1 cells. ESG was taken up by the cells associated with GLUT-1 and activated the Akt/GSK-3β pathway. In vivo, the new bone formation in the calvarial defect was significantly accelerated by ESG and the maternal administration of ESG promoted fetal bone growth. In conclusion, ESG stimulates cell proliferation and differentiation of preosteoblasts via the activation of Akt/GSK-3β signaling and promotes new bone formation in vivo, suggesting that ESG could be a useful stimulant for osteogenesis.

    DOI： 10.1002/jcp.28039

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  • Three-dimensional configuration of apical epithelial compartments including stem cell niches in guinea pig cheek teeth. Reviewed International journal

    Yuta Seino, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Daisuke Koga, Tatsuo Ushiki, Hayato Ohshima

    Journal of oral biosciences   61 ( 1 )   55 - 63   2019.3

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    OBJECTIVES: Continuously growing rodent incisors have an apically located epithelial stem cell compartment, known as an "apical bud" (AB). Few studies have described the morphological features of ABs and stem cell niches in continuously growing premolars/molars. We attempted to clarify the relationship between the three-dimensional configuration of ABs and the stem cell niches in guinea pig cheek teeth. METHODS: We perfusion-fixed four-week-old guinea pigs, then decalcified their premolars/molars to produce serial paraffin sections, which we immunostained for Sox2. We reconstructed the serial sections using image processing and analysis software. We processed undecalcified samples for scanning electron microscopy by KOH digestion. RESULTS: Two types of epithelia with M and Δ shapes surrounded the S-shaped dental papilla in the apical region of the premolars/molars, and there were three Sox2-positive epithelial bulges above the M- and Δ-shaped epithelia. Sox2-positive epithelial stem cell niches were restricted to the apical side, and cell proliferation and differentiation immediately proceeded in the crown-analogue dentin. The Sox2-positive epithelial stem cell niches were sparsely distributed and extended to the occlusal side. We also detected continuously proliferating cells in the cervical loop and Hertwig's epithelial root sheath of the root-analogue dentin. CONCLUSIONS: Our findings suggest that guinea pig cheek teeth have three ABs, and the complex configuration of these types of teeth may be attributed to the prompt formation of crown-analogue dentin followed by the long-term formation of root-analogue dentin.

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  • Craniofacial abnormality with skeletal dysplasia in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-1. Reviewed International journal

    Hiroko Ida-Yonemochi, Wataru Morita, Nobuo Sugiura, Ryosuke Kawakami, Yuki Morioka, Yuka Takeuchi, Toshiya Sato, Shunichi Shibata, Hideto Watanabe, Takeshi Imamura, Michihiro Igarashi, Hayato Ohshima, Kosei Takeuchi

    Scientific reports   8 ( 1 )   17134 - 17134   2018.11

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    Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and plays an important part in organogenesis. To elucidate the roles of CS for craniofacial development, we analyzed the craniofacial morphology in CS N-acetylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. T1KO mice showed the impaired intramembranous ossification in the skull, and the final skull shape of adult mice included a shorter face, higher and broader calvaria. Some of T1KO mice exhibited severe facial developmental defect, such as eye defects and cleft lip and palate, causing embryonic lethality. At the postnatal stages, T1KO mice with severely reduced CS amounts showed malocclusion, general skeletal dysplasia and skin hyperextension, closely resembling Ehlers-Danlos syndrome-like connective tissue disorders. The production of collagen type 1 was significantly downregulated in T1KO mice, and the deposition of CS-binding molecules, Wnt3a, was decreased with CS in extracellular matrices. The collagen fibers were irregular and aggregated, and connective tissues were dysorganized in the skin and calvaria of T1KO mice. These results suggest that CS regulates the shape of the craniofacial skeleton by modulating connective tissue organization and that the remarkable reduction of CS induces hypoplasia of intramembranous ossification and cartilage anomaly, resulting in skeletal dysplasia.

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  • Msx2 Prevents Stratified Squamous Epithelium Formation in the Enamel Organ. Reviewed International journal

    M Nakatomi, H Ida-Yonemochi, C Nakatomi, K Saito, S Kenmotsu, R L Maas, H Ohshima

    Journal of dental research   97 ( 12 )   1355 - 1364   2018.11

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    Tooth enamel is manufactured by the inner enamel epithelium of the multilayered enamel organ. Msx2 loss-of-function mutation in a mouse model causes an abnormal accumulation of epithelial cells in the enamel organ, but the underlying mechanism by which Msx2 regulates amelogenesis is poorly understood. We therefore performed detailed histological and molecular analyses of Msx2 null mice. Msx2 null ameloblasts and stratum intermedium (SI) cells differentiated normally in the early stages of amelogenesis. However, during subsequent developmental stages, the outer enamel epithelium (OEE) became highly proliferative and transformed into a keratinized stratified squamous epithelium that ectopically expressed stratified squamous epithelium markers, including Heat shock protein 25, Loricrin, and Keratin 10. Moreover, expression of hair follicle-specific keratin genes such as Keratin 26 and Keratin 73 was upregulated in the enamel organ of Msx2 mutants. With the accumulation of keratin in the stellate reticulum (SR) region and subsequent odontogenic cyst formation, SI cells gradually lost the ability to differentiate, and the expression of Sox2 and Notch1 was downregulated, leading to ameloblast depolarization. As a consequence, the organization of the Msx2 mutant enamel organ became disturbed and enamel failed to form in the normal location. Instead, there was ectopic mineralization that likely occurred within the SR. In summary, we show that during amelogenesis, Msx2 executes a bipartite function, repressing the transformation of OEE into a keratinized stratified squamous epithelium while simultaneously promoting the development of a properly differentiated enamel organ competent for enamel formation.

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  • Nestin expression is differently regulated between odontoblasts and the subodontoblastic layer in mice. Reviewed International journal

    Mitsushiro Nakatomi, Angela Quispe-Salcedo, Masaka Sakaguchi, Hiroko Ida-Yonemochi, Hideyuki Okano, Hayato Ohshima

    Histochemistry and cell biology   149 ( 4 )   383 - 391   2018.4

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    The Nestin gene encodes type VI intermediate filament and is known to be expressed in undifferentiated cells during neurogenesis and myogenesis. To regulate Nestin expression, the first or second intron enhancer is activated in a tissue-dependent manner, for example, the former in mesodermal cells and the latter in neural stem cells. Although Nestin has also been used as a differentiation marker for odontoblasts during tooth development, how Nestin expression is regulated in odontoblasts remains unclear. Therefore, this study aimed to compare the expression patterns of Nestin-GFP (green fluorescent protein) with that of endogenous Nestin in developing teeth of Nestin-EGFP (enhanced GFP) transgenic mice, in which the second intron enhancer is connected with the EGFP domain, at postnatal 7d, 3w, and 8w. Immunohistochemical and in situ hybridization analyses revealed that endogenous Nestin protein and Nestin mRNA were intensely expressed in differentiated odontoblasts, while GFP immunoreactivity, which reflects the activity of Nestin second intron enhancer-mediated transcription, was mainly observed in the subodontoblastic layer. These results indicate that the first intron enhancer may be activated in differentiated odontoblasts. Intriguingly, Nestin-GFP expression in the subodontoblastic layer was found to be restricted to the coronal pulp of molars, which is susceptible to tooth injuries. Because the subodontoblastic layer serves as a reservoir of newly differentiated odontoblast-like cells upon exogenous stimuli to dentin, our findings suggest that the original odontoblasts and regenerated odontoblast-like cells may differently regulate Nestin expression.

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  • Donor–host tissue interaction in allogenic transplanted tooth germ with special reference to periodontal tissue Reviewed

    Tetsuro Nakaki, Kuniko Nakakura-Ohshima, Eizo Nakagawa, Yuko Ishikawa, Kotaro Saito, Hiroko Ida-Yonemochi, Hayato Ohshima

    Journal of Oral Biosciences   60 ( 1 )   21 - 30   2018.3

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    DOI： 10.1016/j.job.2018.02.002

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  • Donor-host tissue interaction in allogenic transplanted tooth germ with special reference to periodontal tissue Reviewed

    Tetsuro Nakaki, Kuniko Nakakura-Ohshima, Eizo Nakagawa, Yuko Ishikawa, Kotaro Saito, Hiroko Ida-Yonemochi, Hayato Ohshima

    JOURNAL OF ORAL BIOSCIENCES   60 ( 1 )   21 - 30   2018.3

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  • Orthodontic force application upregulated pain-associated prostaglandin-I2/PGI2-receptor/TRPV1 pathway-related gene expression in rat molars. Reviewed

    Mariko Ohkura, Naoto Ohkura, Nagako Yoshiba, Kunihiko Yoshiba, Hiroko Ida-Yonemochi, Hayato Ohshima, Isao Saito, Takashi Okiji

    Odontology   106 ( 1 )   2 - 10   2018.1

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    This study aimed to analyze the mRNA expression and protein localization of prostaglandin I2 (PGI2) synthase (PGIS), the PGI2 receptor (IP receptor) and transient receptor potential cation channel, subfamily V, member 1 (TRPV1) in force-stimulated rat molars, toward the elucidation of the PGI2-IP receptor-TRPV1 pathway that is in operation in the pulp and possibly associated with orthodontic pain and inflammation. Experimental force was applied to the maxillary first and second molars by inserting an elastic band between them for 6-72 h. PGIS, PTGIR (the IP receptor gene), and TRPV1 mRNA levels in the coronal pulp were analyzed with real-time PCR. PGIS, IP receptor, and TRPV1 proteins were immunostained. The force stimulation induced significant upregulation of PGIS at 6-24 h, and PTGIR and TRPV1 at 6 and 12 h in the pulp. PGIS was immunolocalized in odontoblasts and some fibroblasts in the force-stimulated pulp. The IP receptor and TRPV1 immunoreactivities were detected on odontoblasts and some nerve fibers. It was concluded that PGIS, PTGIR, and TRPV1 in rat molar pulp were significantly upregulated shortly after the force application, and that the IP receptor was co-expressed on TRPV1-expressing nerves and odontoblasts. These findings suggest that the PGI2-IP receptor-TRPV1 pathway is associated with the acute phase of force-induced pulp changes involving odontoblasts and nerves.

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  • Quiescent adult stem cells in murine teeth are regulated by Shh signaling. Reviewed International journal

    Yuko Ishikawa, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Hayato Ohshima

    Cell and tissue research   369 ( 3 )   497 - 512   2017.9

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    DOI： 10.1007/s00441-017-2632-x

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  • Effects of pulpotomy using mineral trioxide aggregate on prostaglandin transporter and receptors in rat molars. Reviewed International journal

    Naoto Ohkura, Naoki Edanami, Ryosuke Takeuchi, Aiko Tohma, Mariko Ohkura, Nagako Yoshiba, Kunihiko Yoshiba, Hiroko Ida-Yonemochi, Hayato Ohshima, Takashi Okiji, Yuichiro Noiri

    Scientific reports   7 ( 1 )   6870 - 6870   2017.7

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    Mineral trioxide aggregate (MTA) is a commonly used dental pulp-capping material with known effects in promoting reparative dentinogenesis. However, the mechanism by which MTA induces dentine repair remains unclear. The aim of the present study was to investigate the role of prostaglandin E2 (PGE2) in dentine repair by examining the localisation and mRNA expression levels of its transporter (Pgt) and two of its receptors (Ep2 and Ep4) in a rat model of pulpotomy with MTA capping. Ep2 expression was detected in odontoblasts, endothelial cells, and nerve fibres in normal and pulpotomised tissues, whereas Pgt and Ep4 were immunolocalised only in the odontoblasts. Moreover, mRNA expression of Slco2a1 (encoding Pgt), Ptger2 (encoding Ep2), and Ptger4 (encoding Ep4) was significantly upregulated in pulpotomised dental pulp and trigeminal ganglia after MTA capping. Our results provide insights into the functions of PGE2 via Pgt and Ep receptors in the healing dentine/pulp complex and may be helpful in developing new therapeutic targets for dental disease.

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  • Pannexin 3 regulates proliferation and differentiation of odontoblasts via its hemichannel activities. Reviewed International journal

    Tsutomu Iwamoto, Takashi Nakamura, Masaki Ishikawa, Keigo Yoshizaki, Asuna Sugimoto, Hiroko Ida-Yonemochi, Hayato Ohshima, Masahiro Saito, Yoshihiko Yamada, Satoshi Fukumoto

    PloS one   12 ( 5 )   e0177557   2017

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  • Locally Produced BDNF Promotes Sclerotic Change in Alveolar Bone after Nerve Injury. Reviewed International journal

    Hiroko Ida-Yonemochi, Yurie Yamada, Hiroyuki Yoshikawa, Kenji Seo

    PloS one   12 ( 1 )   e0169201   2017

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  • The Semaphorin 4D-RhoA-Akt Signal Cascade Regulates Enamel Matrix Secretion in Coordination With Cell Polarization During Ameloblast Differentiation. Reviewed International journal

    Keishi Otsu, Hiroko Ida-Yonemochi, Naoki Fujiwara, Hidemitsu Harada

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research   31 ( 11 )   1943 - 1954   2016.11

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    DOI： 10.1002/jbmr.2876

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  • Semaphorin 4D-RhoA-Aktシグナルはエナメル芽細胞分化においてamelogenin分泌と細胞極性を協調的に制御する

    大津 圭史, 依田 浩子, 藤原 尚樹, 原田 英光

    Journal of Oral Biosciences Supplement   2016   205 - 205   2016.9

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  • Osteopontin Is Essential for Type I Collagen Secretion in Reparative Dentin. Reviewed International journal

    K Saito, M Nakatomi, H Ida-Yonemochi, H Ohshima

    Journal of dental research   95 ( 9 )   1034 - 41   2016.8

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    DOI： 10.1177/0022034516645333

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  • The glycogen metabolism via Akt signaling is important for the secretion of enamel matrix in tooth development. Reviewed International journal

    Hiroko Ida-Yonemochi, Keishi Otsu, Hayato Ohshima, Hidemitsu Harada

    Mechanisms of development   139   18 - 30   2016.2

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    DOI： 10.1016/j.mod.2016.01.002

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  • Role of MSX1 in Osteogenic Differentiation of Human Dental Pulp Stem Cells. Reviewed International journal

    Noriko Goto, Katsumi Fujimoto, Sakiko Fujii, Hiroko Ida-Yonemochi, Hayato Ohshima, Takeshi Kawamoto, Mitsuhide Noshiro, Chisa Shukunami, Katsuyuki Kozai, Yukio Kato

    Stem cells international   2016   8035759 - 8035759   2016

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    DOI： 10.1155/2016/8035759

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  • Responses of pulp vasculature after cavity preparation in rat molars Reviewed

    Kotaro Saito, Hiroko Ida-Yonemochi, Tatsuo Ushiki, Hayato Ohshima

    Journal of Oral Biosciences   57 ( 3 )   157 - 164   2015.8

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    DOI： 10.1016/j.job.2015.05.003

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  • The effects of enzymatically synthesized glycogen on the pulpal healing process of extracted teeth following intentionally delayed replantation in mice Reviewed

    Angela Quispe-Salcedo, Hiroko Ida-Yonemochi, Hayato Ohshima

    JOURNAL OF ORAL BIOSCIENCES   57 ( 2 )   124 - 130   2015.5

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    DOI： 10.1016/j.job.2015.01.003

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  • Contribution of donor and host mesenchyme to the transplanted tooth germs. Reviewed International journal

    T Nakaki, K Saito, H Ida-Yonemochi, E Nakagawa, S Kenmotsu, H Ohshima

    Journal of dental research   94 ( 1 )   112 - 20   2015.1

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    DOI： 10.1177/0022034514556536

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  • Effects of a triple antibiotic solution on pulpal dynamics after intentionally delayed tooth replantation in mice. Reviewed International journal

    Angela Quispe-Salcedo, Hiroko Ida-Yonemochi, Hayato Ohshima

    Journal of endodontics   40 ( 10 )   1566 - 72   2014.10

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    DOI： 10.1016/j.joen.2014.05.005

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  • Perlecan-enriched intercellular space of junctional epithelium provides primary infrastructure for leukocyte migration through squamous epithelial cells. Reviewed International journal

    Satoshi Maruyama, Manami Itagaki, Hiroko Ida-Yonemochi, Takehiko Kubota, Manabu Yamazaki, Tatsuya Abé, Hiromasa Yoshie, Jun Cheng, Takashi Saku

    Histochemistry and cell biology   142 ( 3 )   297 - 305   2014.9

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    DOI： 10.1007/s00418-014-1198-x

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  • Establishment of in vitro culture system for evaluating dentin-pulp complex regeneration with special reference to the differentiation capacity of BrdU label-retaining dental pulp cells. Reviewed International journal

    Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Hayato Ohshima

    Histochemistry and cell biology   142 ( 3 )   323 - 33   2014.9

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    DOI： 10.1007/s00418-014-1200-7

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  • Reciprocal expressions between α-dystroglycan and integrin β1, perlecan receptors, in the murine enamel organ development. Reviewed International journal

    Hiroko Ida-Yonemochi, Hidemitsu Harada, Hayato Ohshima, Takashi Saku

    Gene expression patterns : GEP   13 ( 8 )   293 - 302   2013.12

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    DOI： 10.1016/j.gep.2013.05.004

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  • Bcl11b transcription factor plays a role in the maintenance of the ameloblast-progenitors in mouse adult maxillary incisors Reviewed

    Yoshinori Katsuragi, Junko Anraku, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Miki Obata, Yukio Mishima, Yoshiyuki Sakuraba, Yoichi Gondo, Yasumitsu Kodama, Atsushi Nishikawa, Ritsuo Takagi, Hayato Ohshima, Ryo Kominami

    MECHANISMS OF DEVELOPMENT   130 ( 9-10 )   482 - 492   2013.9

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    DOI： 10.1016/j.mod.2013.05.002

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  • Lymphoid enhancer-binding factor 1 expression precedes dentin sialophosphoprotein expression during rat odontoblast differentiation and regeneration. Reviewed International journal

    Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Hayato Ohshima

    Journal of endodontics   39 ( 5 )   612 - 8   2013.5

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    DOI： 10.1016/j.joen.2012.12.016

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  • Use of a triple antibiotic solution affects the healing process of intentionally delayed replanted teeth in mice Reviewed

    Angela Quispe-Salcedo, Hiroko Ida-Yonemochi, Ohshima Hayato

    Journal of Oral Biosciences   55 ( 2 )   91 - 100   2013

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    DOI： 10.1016/j.job.2013.03.001

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  • Loss of keratin 13 in oral carcinoma in situ: a comparative study of protein and gene expression levels using paraffin sections. Reviewed International journal

    Hiroko Ida-Yonemochi, Satoshi Maruyama, Takanori Kobayashi, Manabu Yamazaki, Jun Cheng, Takashi Saku

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   25 ( 6 )   784 - 94   2012.6

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    DOI： 10.1038/modpathol.2011.218

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  • Expression patterns of nestin and dentin sialoprotein during dentinogenesis in mice. Reviewed

    Angela Quispe-Salcedo, Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Hayato Ohshima

    Biomedical research (Tokyo, Japan)   33 ( 2 )   119 - 32   2012.4

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    DOI： 10.2220/biomedres.33.119

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  • The relationship between cell proliferation and differentiation and mapping of putative dental pulp stem/progenitor cells during mouse molar development by chasing BrdU-labeling. Reviewed International journal

    Yuko Ishikawa, Hiroko Ida-Yonemochi, Kuniko Nakakura-Ohshima, Hayato Ohshima

    Cell and tissue research   348 ( 1 )   95 - 107   2012.4

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    DOI： 10.1007/s00441-012-1347-2

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  • Glucose uptake mediated by glucose transporter 1 is essential for early tooth morphogenesis and size determination of murine molars. Reviewed International journal

    Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Hidemitsu Harada, Hiroki Takata, Otto Baba, Hayato Ohshima

    Developmental biology   363 ( 1 )   52 - 61   2012.3

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    DOI： 10.1016/j.ydbio.2011.12.020

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  • CT anatomy of the anterior superior alveolar nerve canal: A macroscopic and microscopic study Reviewed

    Ray Tanaka, Takafumi Hayashi, Hayato Ohshima, Hiroko Ida-Yonemochi, Shin-Ichi Kenmotsu, Makiko Ike

    Oral Radiology   27 ( 2 )   93 - 97   2011.12

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    DOI： 10.1007/s11282-011-0067-8

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  • Responses of BrdU label-retaining dental pulp cells to allogenic tooth transplantation into mouse maxilla. Reviewed International journal

    Noriko Mutoh, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Eizo Nakagawa, Nobuyuki Tani-Ishii, Hayato Ohshima

    Histochemistry and cell biology   136 ( 6 )   649 - 61   2011.12

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    DOI： 10.1007/s00418-011-0868-1

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  • Morphogenetic roles of perlecan in the tooth enamel organ: an analysis of overexpression using transgenic mice. Reviewed International journal

    Hiroko Ida-Yonemochi, Ichiro Satokata, Hayato Ohshima, Toshiya Sato, Minesuke Yokoyama, Yoshihiko Yamada, Takashi Saku

    Matrix biology : journal of the International Society for Matrix Biology   30 ( 7-8 )   379 - 88   2011.9

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    DOI： 10.1016/j.matbio.2011.08.001

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  • Differential expression of perlecan receptors, α-dystroglycan and integrin β1, before and after invasion of oral squamous cell carcinoma. Reviewed International journal

    Md Shahidul Ahsan, Manabu Yamazaki, Satoshi Maruyama, Takanori Kobayashi, Hiroko Ida-Yonemochi, Mayumi Hasegawa, Adeola Henry Ademola, Jun Cheng, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   40 ( 7 )   552 - 9   2011.8

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  • Nuclear translocation of β-catenin synchronized with loss of E-cadherin in oral epithelial dysplasia with a characteristic two-phase appearance. Reviewed International journal

    Carlos G Alvarado, Satoshi Maruyama, Jun Cheng, Hiroko Ida-Yonemochi, Takanori Kobayashi, Manabu Yamazaki, Ritsuo Takagi, Takashi Saku

    Histopathology   59 ( 2 )   283 - 91   2011.8

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  • Differentiation capacity of BrdU label-retaining dental pulp cells during pulpal healing following allogenic transplantation in mice. Reviewed

    Kotaro Saito, Yuko Ishikawa, Kuniko Nakakura-Ohshima, Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Shin-Ichi Kenmotsu, Hayato Ohshima

    Biomedical research (Tokyo, Japan)   32 ( 4 )   247 - 57   2011.8

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  • The expression of GM-CSF and osteopontin in immunocompetent cells precedes the odontoblast differentiation following allogenic tooth transplantation in mice. Reviewed International journal

    Kotaro Saito, Mitsushiro Nakatomi, Hiroko Ida-Yonemochi, Shin-ichi Kenmotsu, Hayato Ohshima

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society   59 ( 5 )   518 - 29   2011.5

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  • O40-responses of BrdU-label-retaining dental pulp cells to allogenic tooth transplantation into mouse maxilla. Reviewed International journal

    N Mutoh, M Nakatomi, H Ida-Yonemochi, E Nakagawa, N Tani-Ishii, H Ohshima

    Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie   49 ( 3 )   93 - 93   2011.4

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  • O39-establishment of in vitro culture system for evaluation of the dentin-pulp complex regeneration with special reference to differentiation capacity of the BrdU-label-retaining dental pulp cells. Reviewed International journal

    H Onshima, E Nakagawa, H Ida-Yonemochi

    Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie   49 ( 3 )   92 - 92   2011.4

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  • O36-the expression of GM-CSF and osteopontin in immunocompetent cells precedes the odontoblast differentiation following allogenic tooth transplantation in mice. Reviewed International journal

    K Saito, M Nakatomi, H Ida-Yonemochi, S Kenmotsu, H Ohshima

    Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie   49 ( 3 )   91 - 91   2011.4

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  • O5-differential expression and functional significance of glucose transporters during murine tooth development. Reviewed International journal

    Hiroko Ida-Yonemochi, Mitsushiro Nakatomi, Hidemitsu Harada, Hayato Ohshima

    Bulletin du Groupement international pour la recherche scientifique en stomatologie & odontologie   49 ( 3 )   86 - 86   2011.4

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  • Differential expression profiles between α-dystroglycan and integrin β1 in ameloblastoma: two possible perlecan signalling pathways for cellular growth and differentiation. Reviewed International journal

    Hiroko Ida-Yonemochi, Md Shahidul Ahsan, Takashi Saku

    Histopathology   58 ( 2 )   234 - 45   2011.1

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    DOI： 10.1111/j.1365-2559.2010.03732.x

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  • Heparanase, heparan sulfate and perlecan distribution along with the vascular penetration during stellate reticulum retraction in the mouse enamel organ. Reviewed International journal

    Hiroko Ida-Yonemochi, Motowo Nakajima, Takashi Saku

    Archives of oral biology   55 ( 10 )   778 - 87   2010.10

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    DOI： 10.1016/j.archoralbio.2010.07.002

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  • Mapping of BrdU label-retaining dental pulp cells in growing teeth and their regenerative capacity after injuries. Reviewed International journal

    Yuko Ishikawa, Hiroko Ida-Yonemochi, Hironobu Suzuki, Kuniko Nakakura-Ohshima, Han-Sung Jung, Masaki J Honda, Yumiko Ishii, Nobukazu Watanabe, Hayato Ohshima

    Histochemistry and cell biology   134 ( 3 )   227 - 41   2010.9

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    DOI： 10.1007/s00418-010-0727-5

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  • Histopathological varieties of oral carcinoma in situ: Diagnosis aided by immunohistochemistry dealing with the second basal cell layer as the proliferating center of oral mucosal epithelia. Reviewed International journal

    Takanori Kobayashi, Satoshi Maruyama, Jun Cheng, Hiroko Ida-Yonemochi, Minoru Yagi, Ritsuo Takagi, Takashi Saku

    Pathology international   60 ( 3 )   156 - 66   2010.3

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    DOI： 10.1111/j.1440-1827.2009.02499.x

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  • Oral solitary fibrous tumor: a cytogenetic analysis of tumor cells in culture with literature review. Reviewed International journal

    Wael M Swelam, Jun Cheng, Hiroko Ida-Yonemochi, Satoshi Maruyama, Takashi Saku

    Cancer genetics and cytogenetics   194 ( 2 )   75 - 81   2009.10

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    DOI： 10.1016/j.cancergencyto.2009.05.003

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  • Matrix metalloproteinase 7 and perlecan in oral epithelial dysplasia and carcinoma in situ: an aid for histopathologic recognition of their cell proliferation centers. Reviewed International journal

    W M Tilakaratne, T Kobayashi, H Ida-Yonemochi, W Swelam, M Yamazaki, T Mikami, C G Alvarado, A Md Shahidul, S Maruyama, J Cheng, T Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   38 ( 4 )   348 - 55   2009.4

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    DOI： 10.1111/j.1600-0714.2009.00750.x

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  • Perlecan-rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor. Reviewed International journal

    Masayuki Tsuneki, Jun Cheng, Satoshi Maruyama, Hiroko Ida-Yonemochi, Motowo Nakajima, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   37 ( 5 )   287 - 93   2008.5

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    DOI： 10.1111/j.1600-0714.2007.00620.x

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  • Laminin alpha 5 is required for dental epithelium growth and polarity and the development of tooth bud and shape Reviewed

    S Fukumoto, JH Miner, H Ida, E Fukumoto, K Yuasa, H Miyazaki, MP Hoffman, Y Yamada

    JOURNAL OF BIOLOGICAL CHEMISTRY   281 ( 8 )   5008 - 5016   2006.2

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    DOI： 10.1074/jbc.M509295200

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  • Perlecan, a Heparan Sulfate Proteoglycan, Is a Major Constituent of the Intraepithelial Stroma Functioning in Tooth Morphogenesis Reviewed

    Hiroko Ida-Yonemochi, Takashi Saku

    Journal of Oral Biosciences   48 ( 4 )   233 - 243   2006

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    DOI： 10.2330/joralbiosci.48.233

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  • Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization. Reviewed International journal

    Hiroko Utsunomiya, Wanninayake M Tilakaratne, Kazufumi Oshiro, Satoshi Maruyama, Makoto Suzuki, Hiroko Ida-Yonemochi, Jun Cheng, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   34 ( 8 )   498 - 507   2005.9

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    DOI： 10.1111/j.1600-0714.2005.00339.x

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  • Vascular endothelial growth factor in salivary pleomorphic adenomas: one of the reasons for their poorly vascularized stroma. Reviewed International journal

    Wael Swelam, Hiroko Ida-Yonemochi, Satoshi Maruyama, Kazufumi Ohshiro, Jun Cheng, Takashi Saku

    Virchows Archiv : an international journal of pathology   446 ( 6 )   653 - 62   2005.6

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    DOI： 10.1007/s00428-005-1219-1

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  • Perlecan, a basement membrane-type heparan sulfate proteoglycan, in the enamel organ: its intraepithelial localization in the stellate reticulum. Reviewed International journal

    Hiroko Ida-Yonemochi, Kazufumi Ohshiro, Wael Swelam, Hamdy Metwaly, Takashi Saku

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society   53 ( 6 )   763 - 72   2005.6

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    DOI： 10.1369/jhc.4A6479.2005

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  • GD3 synthase gene found expressed in dental epithelium and shown to regulate cell proliferation. Reviewed International journal

    Aya Yamada, Emiko Fukumoto, Yoko Kamasaki, Hiroko Ida-Yonemochi, Takashi Saku, Taku Fujiwara, Satoshi Fukumoto

    Archives of oral biology   50 ( 4 )   393 - 9   2005.4

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    DOI： 10.1016/j.archoralbio.2004.09.014

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  • Two-phase appearance of oral epithelial dysplasia resulting from focal proliferation of parabasal cells and apoptosis of prickle cells. Reviewed International journal

    Mei Syafriadi, Jun Cheng, Kai Yu Jen, Hiroko Ida-Yonemochi, Makoto Suzuki, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   34 ( 3 )   140 - 9   2005.3

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    DOI： 10.1111/j.1600-0714.2004.00283.x

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  • Angiolipoma of the buccal mucosa: a possible role of mast cell-derived VEGF in its enhanced vascularity. Reviewed International journal

    Hiroko Ida-Yonemochi, Wael Swelam, Chikara Saito, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   34 ( 1 )   59 - 61   2005.1

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    DOI： 10.1111/j.1600-0714.2004.00230.x

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  • Angiogenesis in mucous retention cyst: a human in vivo-like model of endothelial cell differentiation in mucous substrate. Reviewed International journal

    Wael Swelam, Hiroko Ida-Yonemochi, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   34 ( 1 )   30 - 8   2005.1

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    DOI： 10.1111/j.1600-0714.2004.00282.x

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  • Recruitment of osteoclasts in the mandible of osteopetrotic (op/op) mice. Reviewed International journal

    Hiroko Ida-Yonemochi, Osamu Ishibashi, Hideaki Sakai, Takashi Saku

    European journal of oral sciences   112 ( 2 )   148 - 55   2004.4

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    DOI： 10.1111/j.0909-8836.2004.00109.x

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  • Intraepithelial expression of perlecan, a basement membrane-type heparan sulfate proteoglycan reflects dysplastic changes of the oral mucosal epithelium. Reviewed International journal

    Terué Ikarashi, Hiroko Ida-Yonemochi, Kazufumi Ohshiro, Jun Cheng, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   33 ( 2 )   87 - 95   2004.2

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    DOI： 10.1111/j.1600-0714.2004.00026.x

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  • Solitary fibrous tumor of the lower lip involving minor salivary gland components: Report of a case and review of the literature of salivary gland cases

    Wael Swelam, Hiroko Ida-Yonemochi, Satoshi Maruyama, Terué Ikarashi, Junichi Fukuda, Ritsuo Takagi, Takafumi Hayashi, Takashi Saku

    Oral Oncology Extra   40 ( 10 )   107 - 112   2004

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    DOI： 10.1016/j.ooe.2004.06.002

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  • Varieties of pericoronal hamartoma: the concept of the disease entity revisited. Reviewed International journal

    Hiroko Ida-Yonemochi, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   32 ( 10 )   618 - 9   2003.11

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  • Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis Reviewed

    M Nagata, H Fujita, H Ida, H Hoshina, T Inoue, Y Seki, M Ohnishi, T Ohyama, S Shingaki, M Kaji, T Saku, R Takagi

    INTERNATIONAL JOURNAL OF CANCER   106 ( 5 )   683 - 689   2003.9

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    DOI： 10.1002/ijc.11283

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  • Vascular endothelial cell participation in formation of lymphoepithelial lesions (epi-myoepithelial islands) in lymphoepithelial sialadenitis (benign lymphoepithelial lesion). Reviewed International journal

    Hamdy Metwaly, Jun Cheng, Hiroko Ida-Yonemochi, Kazufumi Ohshiro, Kai Yu Jen, Ai Ru Liu, Takashi Saku

    Virchows Archiv : an international journal of pathology   443 ( 1 )   17 - 27   2003.7

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    DOI： 10.1007/s00428-003-0824-0

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  • Congenital defect of maxillary primary central incisor associated with exposed pulp and gingival [fibrosis]: case report. Reviewed International journal

    Tomiko Sano, Mieko Tomizawa, Hiroko Ida-Yonemochi, Yoshihiro Tanabe, Tadashi Noda

    The Journal of clinical pediatric dentistry   28 ( 1 )   39 - 42   2003

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  • Precancerous foci in pleomorphic adenoma of the salivary gland: recognition of focal carcinoma and atypical tumor cells by P53 immunohistochemistry Reviewed

    S Ohtake, J Cheng, H Ida, M Suzuki, K Ohshiro, WG Zhang, T Saku

    JOURNAL OF ORAL PATHOLOGY & MEDICINE   31 ( 10 )   590 - 597   2002.11

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  • The basement membrane-type heparan sulfate proteoglycan (perlecan) in ameloblastomas: its intercellular localization in stellate reticulum-like foci and biosynthesis by tumor cells in culture. Reviewed International journal

    Hiroko Ida-Yonemochi, Terué Ikarashi, Masaki Nagata, Hideyuki Hoshina, Ritsuo Takagi, Takashi Saku

    Virchows Archiv : an international journal of pathology   441 ( 2 )   165 - 73   2002.8

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    DOI： 10.1007/s00428-001-0556-y

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  • Disturbed tooth eruption in osteopetrotic (op/op) mice: histopathogenesis of tooth malformation and odontomas. Reviewed International journal

    Hiroko Ida-Yonemochi, Tadashi Noda, Hitoyata Shimokawa, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   31 ( 6 )   361 - 73   2002.7

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    DOI： 10.1034/j.1600-0714.2002.00087.x

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  • No developmental failure of cultured tooth germs from osteopetrotic (op/op) mice. Reviewed International journal

    Hiroko Ida-Yonemochi, Takashi Saku

    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology   31 ( 6 )   374 - 8   2002.7

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    DOI： 10.1034/j.1600-0714.2002.00138.x

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  • Enhanced expression of basement-membrane-type heparan sulfate proteoglycan in tumor fibro-myxoid stroma of intrahepatic cholangiocarcinoma

    H Sabit, K Tsuneyama, T Shimonishi, K Harada, J Cheng, H Ida, T Saku, K Saito, Y Nakanuma

    PATHOLOGY INTERNATIONAL   51 ( 4 )   248 - 256   2001.4

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    DOI： 10.1046/j.1440-1827.2001.01201.x

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  • Perlecan (heparan sulfate proteoglycan) gene expression reflected in the characteristic histological architecture of salivary adenoid cystic carcinoma

    S Kimura, J Cheng, H Ida, N Hao, Y Fujimori, T Saku

    VIRCHOWS ARCHIV-AN INTERNATIONAL JOURNAL OF PATHOLOGY   437 ( 2 )   122 - 128   2000.8

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  • Melanotic neuroectodermal tumor of infancy in the mandible: report of a case. Reviewed International journal

    Y Hoshina, Y Hamamoto, I Suzuki, T Nakajima, H Ida-Yonemochi, T Saku

    Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics   89 ( 5 )   594 - 9   2000.5

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  • 歯科治療中に発生した医原性外来異物迷入の6例

    島村 拓也, 中條 智恵, 高田 真仁, 野村 務, 中島 民雄, 依田 浩子

    新潟歯学会雑誌   29 ( 2 )   161 - 167   1999.12

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  • Effects of synthetic CpG oligodeoxynucleotides on the healing process of heavily injured tooth pulp

    ANGELA Quispe-Salcedo, ANGELA Quispe-Salcedo, 山崎智彦, 依田浩子, 大島勇人

    日本再生医療学会総会(Web)   22nd   2023

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  • 大理石骨病モデルマウスを用いた歯の病態解析

    原田英光, 池崎晶二郎, 後藤(松元)奈緒美, 中西(松井)真弓, 和田洋, 孫(和田)戈虹, 依田浩子, 大島勇人, 大津圭史

    日本実験動物学会総会講演要旨集(Web)   69th   2022

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  • モルモット臼歯における上皮幹細胞ニッチを含む形成端上皮コンパートメントの三次元立体構築 Reviewed

    清野 雄多, 依田 浩子, 大島 勇人

    新潟歯学会雑誌   49 ( 2 )   85 - 85   2019.12

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  • 歯胚上皮及び歯髄幹細胞・象牙芽細胞維持に関わるShh-Ptch-Gliシグナル経路 Reviewed

    石川 裕子, 依田 浩子, 斎藤 浩太郎, 中富 満城, 大島 勇人

    Journal of Oral Biosciences Supplement   2019   368 - 368   2019.10

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  • 肥満型2型糖尿病モデルTSODマウスにおける口腔組織の経時的変化 Reviewed

    依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2019   169 - 169   2019.10

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  • マウス歯肉接合上皮細胞の由来と動態について

    斎藤 浩太郎, 依田 浩子, 大島 邦子, 大島 勇人

    Journal of Oral Biosciences Supplement   2018   278 - 278   2018.9

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  • マウス切歯・臼歯の静的幹細胞維持に関わるShhシグナルの役割

    石川 裕子, 依田 浩子, 斎藤 浩太郎, 中富 満城, 大島 勇人

    Journal of Oral Biosciences Supplement   2018   176 - 176   2018.9

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  • 組織連続切片三次元構築法とBrdUラベリングを用いたモルモット臼歯apical budにおける歯胚上皮幹細胞と一過性増殖細胞分布の観察

    清野 雄多, 中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2018   291 - 291   2018.9

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  • 軟骨細胞特異的オートファジー不全マウスは四肢の成長障害を生じる-第2報-

    堀米洋二, 堀米洋二, 小松雅明, 依田浩子, 和栗聡, 遠藤直人

    日本整形外科学会雑誌   92 ( 3 )   2018

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  • 他家歯胚移植におけるドナー・ホスト相互作用 歯周組織に着目して

    中木 哲朗, 大島 邦子, 石川 裕子, 斎藤 浩太郎, 依田 浩子, 大島 勇人

    新潟歯学会雑誌   47 ( 2 )   121 - 121   2017.12

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  • 酸素濃度依存的Sox2-RhoAシグナルによるエナメル上皮幹細胞制御機構

    大津 圭史, 依田 浩子, 藤原 尚樹, 大島 勇人, 原田 英光

    生命科学系学会合同年次大会   2017年度   [4P2T16 - 0815)]   2017.12

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  • 組織連続切片三次元構築法とBrdUラベリングによるモルモット臼歯apical budの観察 Reviewed

    清野 雄多, 中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2017   222 - 222   2017.9

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  • 歯の形成過程におけるAMP-activated protein kinase(AMPK)の発現と機能

    依田 浩子, 大津 圭史, 原田 英光, 大島 勇人

    Journal of Oral Biosciences Supplement   2017   432 - 432   2017.9

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  • 軟骨細胞特異的オートファジー不全マウスは四肢の成長障害を生じる

    堀米洋二, 小松雅明, 依田浩子, 遠藤直人

    日本整形外科学会雑誌   91 ( 8 )   2017

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  • コンドロイチン硫酸は頭蓋顔面形態形成を制御している

    依田 浩子, 森田 航, 柴田 俊一, 大島 勇人, 武内 恒成

    Journal of Oral Biosciences Supplement   2016   466 - 466   2016.9

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  • 象牙芽細胞におけるNestin遺伝子の発現制御機構

    中富 満城, Quispe-Salcedo Angela, 依田 浩子, 大島 勇人, 岡野 栄之

    Journal of Oral Biosciences Supplement   2016   471 - 471   2016.9

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  • エナメル質の高度石灰化の謎 成熟期エナメル芽細胞の理解への挑戦 成熟期エナメル芽細胞でのV-ATPaseの機能と高度石灰化との関連

    原田 英光, 依田 浩子, 佐原 資謹, 大島 勇人, 藤原 尚樹, 大津 圭史, 松元 奈緒美, 中西 真弓

    Journal of Oral Biosciences Supplement   2016   80 - 80   2016.9

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  • 象牙芽細胞におけるNestin遺伝子の発現制御機構

    中富満城, QUISPE-SALCEDO Angela, 依田浩子, 大島勇人

    Journal of Oral Biosciences Supplement (Web)   2016   2016

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  • 歯髄幹細胞においてホメオボックス型転写因子MSX1はコレステロール合成関連遺伝子の発現を制御する

    五藤 紀子, 藤本 勝巳, 藤井 紗貴子, 依田 浩子, 持, 大島 勇人, 河本 健, 能城 光秀, 宿南 知佐, 香西 克之, 加藤 幸夫

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [2P1015] - [2P1015]   2015.12

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  • 実験的歯の移動におけるラット臼歯歯髄内prostaglandin I2合成酵素と受容体の発現解析

    大倉 麻里子, 大倉 直人, 吉羽 永子, 吉羽 邦彦, 依田 浩子, 大島 勇人, 齋藤 功, 興地 隆史

    新潟歯学会雑誌   45 ( 2 )   97 - 98   2015.12

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  • Aktシグナルがグルコース代謝を促進しエナメル芽細胞分化を誘導する

    依田 浩子, 米持, 大津 圭史, 大島 勇人, 原田 英光

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [1P0940] - [1P0940]   2015.12

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  • ラット臼歯歯髄断髄後のProstaglandin Transporterに対する免疫組織学的局在解析

    大倉 直人, 枝並 直樹, 吉羽 永子, 吉羽 邦彦, 依田 浩子, 大島 勇人, 興地 隆史

    Journal of Oral Biosciences Supplement   2015   367 - 367   2015.9

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  • Dentin Sialophosphoprotein(DSPP)を形態と機能から考える 象牙芽細胞分化過程におけるDsppの機能的意義

    斎藤 浩太郎, 中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2015   128 - 128   2015.9

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  • エナメル芽細胞分化過程におけるナトリウム依存性グルコース輸送体の局在と機能

    依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2015   179 - 179   2015.9

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  • ラット臼歯歯髄断髄後のProstaglandin Transporterに対する免疫組織学的局在解析

    大倉直人, 枝並直樹, 吉羽永子, 吉羽邦彦, 依田浩子, 大島勇人, 興地隆史

    Journal of Oral Biosciences Supplement (Web)   2015   2015

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  • ホメオボックス型転写因子MSX1による歯髄幹細胞の象牙芽細胞/骨芽細胞分化制御

    五藤 紀子, 藤本 勝巳, 依田 浩子, 大島 勇人, 河本 健, 能城 光秀, 宿南 知佐, 香西 克之, 加藤 幸夫

    日本生化学会大会プログラム・講演要旨集   87回   [4P - 345]   2014.10

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  • ヒト歯髄におけるプロスタグランジンE2輸送担体および特異的レセプターの免疫組織化学的局在解析

    大倉 直人, 大倉 麻里子, 吉羽 永子, 吉羽 邦彦, 小田 陽平, 依田 浩子, 大島 勇人, 興地 隆史

    Journal of Oral Biosciences Supplement   2014   183 - 183   2014.9

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  • マウスMsx2遺伝子は外エナメル上皮の角化重層扁平上皮化を抑制する

    中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2014   196 - 196   2014.9

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  • マウス臼歯歯胚移植後の歯髄発生過程におけるホスト・ドナー相互作用について

    斎藤 浩太郎, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2014   140 - 140   2014.9

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  • ヒト歯髄におけるプロスタグランジンE<sub>2</sub>輸送担体および特異的レセプターの免疫組織化学的局在解析

    大倉直人, 大倉麻里子, 吉羽永子, 吉羽邦彦, 小田陽平, 依田浩子, 大島勇人, 興地隆史

    Journal of Oral Biosciences Supplement (Web)   2014   2014

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  • 酵素合成グリコーゲンによる歯の再植後の歯髄治癒促進効果について

    大島勇人, QUISPE-SALCEDO Angela, 高田洋樹, 依田浩子

    再生医療   13   2014

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  • マウスのエナメル芽細胞の極性維持に関するMsx2遺伝子の機能

    中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2013   118 - 118   2013.9

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  • マウスの意図的に遅延した歯の生え替わり後の治癒過程に対する酵素的に合成したグリコーゲン(ESG)の有効性(Effectiveness of Enzymatically Synthesized Glycogen (ESG) on the healing process following intentionally-delayed tooth replantation in mice)

    Quispe-Salcedo Angela, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2013   123 - 123   2013.9

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  • AKTシグナルがグリコーゲン代謝を促進しエナメル芽細胞分化を誘導する

    依田 浩子, 大島 勇人, 原田 英光

    Journal of Oral Biosciences Supplement   2013   191 - 191   2013.9

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  • マウス歯胚他家移植後の歯髄構成細胞集団の生後変化

    中木 哲朗, 斎藤 浩太郎, 中川 英蔵, 依田 浩子, 大島 勇人

    新潟歯学会雑誌   42 ( 2 )   133 - 134   2012.12

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  • 意図的に遅延した歯の再植後の歯髄の治癒過程における抗菌薬の有効性(Effectiveness of antimicrobials in the pulpal healing process following intentionally delayed tooth replantation)

    Quispe-Salcedo Angela, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2012   85 - 85   2012.9

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  • マウス切歯のエナメル質形成過程におけるMsx2遺伝子の機能

    中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences Supplement   2012   122 - 122   2012.9

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  • マウス唾液腺分化過程におけるグリコーゲン代謝の役割

    依田 浩子, 中川 英蔵, 大島 勇人

    Journal of Oral Biosciences Supplement   2012   89 - 89   2012.9

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  • マウス歯胚他家移植実験を用いた歯髄構成細胞集団の生後変化の解明

    大島 勇人, 中木 哲朗, 斎藤 浩太郎, 中川 英蔵, 依田 浩子

    Journal of Oral Biosciences Supplement   2012   84 - 84   2012.9

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  • ラット象牙芽細胞の分化過程および再生過程におけるLef1遺伝子の発現

    中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences   53 ( Suppl. )   127 - 127   2011.9

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  • 酵素合成グリコーゲンはin vitroおよびin vivoで骨形成を促進する

    依田 浩子, 監物 新一, 織田 公光, 大島 勇人

    Journal of Oral Biosciences   53 ( Suppl. )   191 - 191   2011.9

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  • マウス他家移植後の歯髄治癒過程における歯髄組織幹細胞の分化能および細胞増殖とアポトーシスとの関連

    斎藤 浩太郎, 依田 浩子, 中富 満城, 大島 勇人

    Journal of Oral Biosciences   53 ( Suppl. )   128 - 128   2011.9

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  • 象牙質形成時と加齢時のnestinとdentin sialoprotein発現パターンの評価(Assessment of nestin and dentin sialoprotein expression patterns during dentinogenesis and aging)

    Quispe Salcedo Angela, 依田 浩子, 中富 満城, 大島 勇人

    Journal of Oral Biosciences   53 ( Suppl. )   150 - 150   2011.9

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  • マウス臼歯他家移植後の象牙芽細胞分化過程における免疫細胞によるGM-CSFおよびオステオポンチンの発現

    斎藤 浩太郎, 中富 満城, 依田 浩子, 大島 勇人

    新潟歯学会雑誌   41 ( 1 )   52 - 52   2011.6

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  • Bcl11b点変異アリルとKOアリルを持つマウスに認められる切歯発育異常

    安樂 純子, 葛城 美徳, 中富 満城, 依田 浩子, 持, 西川 敦, 児玉 泰光, 大島 勇人, 木南 凌, 高木 律男

    日本口腔科学会雑誌   60 ( 1 )   124 - 124   2011.1

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  • マウス臼歯他家移植後の象牙芽細胞分化過程における免疫細胞によるGM-CSFとオステオポンチンの発現

    斎藤 浩太郎, 中富 満城, 依田 浩子, 大島 勇人

    Journal of Oral Biosciences   52 ( Suppl )   121 - 121   2010.9

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  • 象牙質・歯髄複合体培養法による歯髄再生モデルの確立と歯髄組織幹細胞の動態

    依田 浩子, 中富 満城, 大島 勇人

    Journal of Oral Biosciences   52 ( Suppl )   122 - 122   2010.9

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  • Bcl11b点変異アリルとKOアリルを持つマウスに認められる切歯発育異常

    安樂 純子, 葛城 美徳, 中富 満城, 依田 浩子, 持, 西川 敦, 児玉 泰光, 大島 勇人, 木南 凌, 高木 律男

    新潟歯学会雑誌   40 ( 1 )   97 - 97   2010.6

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  • マウス歯胚発育におけるグルコース輸送体の局在と機能

    依田 浩子, 中富 満城, 中川 英蔵, 大島 勇人

    解剖学雑誌   85 ( Suppl. )   175 - 175   2010.3

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  • ラット切歯歯髄象牙芽細胞層内樹状細胞の防御機能について

    塩生 有希, 依田 浩子, 大島 勇人

    解剖学雑誌   85 ( Suppl. )   202 - 202   2010.3

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  • ラット臼歯象牙質形成における歯髄毛細血管と基質形成・石灰化との相関について

    大島 勇人, 中富 満城, 中川 英蔵, 石川 裕子, 監物 新一, 依田 浩子

    解剖学雑誌   85 ( Suppl. )   110 - 110   2010.3

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  • マウス臼歯発生過程における歯髄組織幹細胞の局在

    石川 裕子, 依田 浩子, 大島 邦子, 本田 雅規, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   75 - 75   2009.8

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  • マウス臼歯再植・移植後の歯髄治癒過程におけるGM-CSFおよびオステオポンチンの役割について

    斎藤 浩太郎, 依田 浩子, 石川 裕子, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   97 - 97   2009.8

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  • マウス顎骨への歯の他家移植後の歯髄・歯周組織再生過程における組織幹細胞の動態について

    武藤 徳子, 中川 英蔵, 依田 浩子, 石井 信之, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   98 - 98   2009.8

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  • マウス臼歯再植・移植後の歯髄治癒過程におけるGM-CSFおよびオステオポンチンの役割について

    斎藤 浩太郎, 依田 浩子, 石川 裕子, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   90 - 90   2009.8

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  • マウス顎骨への歯胚他家移植後の歯周組織形成過程について

    中川 英蔵, 依田 浩子, 吉江 弘正, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   91 - 91   2009.8

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  • マウス顎骨への歯の他家移植後の歯髄・歯周組織再生過程における組織幹細胞の動態について

    武藤 徳子, 中川 英蔵, 依田 浩子, 石井 信之, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   75 - 75   2009.8

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  • マウス歯胚発育過程におけるグリコーゲンおよびグルコース輸送体の局在

    依田 浩子, 中川 英蔵, 馬場 麻人, 織田 公光, 寺島 達夫, 大島 勇人

    Journal of Oral Biosciences   51 ( Suppl. )   90 - 90   2009.8

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  • マウス舌下部への臼歯および歯冠部の他家移植後の歯髄組織幹細胞の動態と硬組織形成能について

    大島 勇人, 石川 裕子, 鈴木 啓展, 依田 浩子, 監物 新一, 大島 邦子

    解剖学雑誌   84 ( Suppl. )   140 - 140   2009.3

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  • 下顎骨に生じた中心性巨細胞肉芽腫の1例

    小山 貴寛, 高木 律男, 永田 昌毅, 飯田 明彦, 児玉 泰光, 林 孝文, 依田 浩子, 朔 敬

    日本口腔外科学会雑誌   54 ( Suppl. )   96 - 96   2008.9

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  • CK17と14‐3‐3σの共発現が口腔粘膜扁平上皮癌で強調される

    三上俊彦, CHENG Jun, 丸山智, 小林孝憲, 依田浩子, 新垣晋, 齊藤力, 朔敬

    日本臨床口腔病理学会総会・学術大会プログラム・抄録集   19th   69   2008.8

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  • 口腔粘膜扁平上皮癌・上皮内癌の再発に関する臨床病理学的検討

    小林 孝憲, 依田 浩子, 丸山 智, 程 くん, 齊藤 力, 高木 律男, 朔 敬

    日本病理学会会誌   97 ( 1 )   320 - 320   2008.3

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  • 口腔粘膜上皮悪性境界病変におけるいわゆる幹細胞マーカ分子の発現様式

    小林 孝憲, 依田 浩子, 船山 昭典, 丸山 智, 程 君, 高木 律男, 朔 敬

    日本病理学会会誌   95 ( 1 )   288 - 288   2006.4

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  • 口腔粘膜悪性境界病変の病理組織学的診断根拠としての機能性分子発現様式の解析

    小林 孝憲, 依田 浩子, 丸山 智, 程 くん, 高木 律男, 朔 敬

    新潟歯学会雑誌   35 ( 2 )   247 - 247   2006.1

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  • 歯原性角化嚢胞モデルとしてのMsx2ノックアウトマウス顎骨嚢胞

    朔 敬, 板垣 真奈美, 依田 浩子, 丸山 智, 程 君, 大島 勇人, 里方 一郎

    Journal of Oral Biosciences   47 ( Suppl. )   96 - 96   2005.9

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  • 口腔粘膜扁平上皮癌の浸潤とは腫瘍間質が誘導されることと同義である

    小林 孝憲, 依田 浩子, 程 君, 高木 律男, 朔 敬

    日本病理学会会誌   94 ( 1 )   249 - 249   2005.3

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  • Perlecan, a basement membrane type heparan sulfate proteoglycan, in the epithelial space: a possibility of a new concept of intraepithelial stroma

    Ida Hiroko, Saku Takashi

    Niigata dental journal   34 ( 2 )   83 - 85   2004.12

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    Other Link： http://search.jamas.or.jp/link/ui/2006109734

  • 歯肉接合上皮層内には細胞外基質が存在する

    板垣 真奈美, 依田 浩子, 朔 敬

    Journal of oral biosciences   46 ( 5 )   455 - 455   2004.9

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  • パールカンは歯胚エナメル器の発育分化を制御している : 過剰発現系トランスジェニックマウスによる解析

    依田 浩子, 里方 一郎, 朔 敬

    Journal of oral biosciences   46 ( 5 )   452 - 452   2004.9

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  • ラミニンによる咬頭形成の分子メカニズムの解明

    福本 敏, 依田 浩子, 藤原 卓

    小児歯科学雑誌   42 ( 2 )   190 - 190   2004

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    DOI： 10.11411/jspd1963.42.2_190

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  • Lymphoid cells and carcinoma cells contribute to the formation of fibrous stroma in salivary gland lymphoepithelial carcinomas

    Jen KaiYu

    Japanese journal of oral biology   45 ( 5 )   317 - 317   2003.9

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  • マウス歯胚歯乳頭由来血管内皮前駆細胞

    依田 浩子, 朔 敬

    歯科基礎医学会雑誌   45 ( 5 )   296 - 296   2003.9

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  • 口腔扁平上皮癌のリンパ節転移予測因子としてのMMP-1遺伝子発現定量

    永田 昌毅, 星名 秀行, 藤田 一, 関 雪絵, 長島 克弘, 小玉 直樹, 大西 真, 新垣 晋, 斎藤 力, 依田 浩子, 朔 敬, 高木 律男

    新潟歯学会雑誌   33 ( 1 )   74 - 74   2003.7

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  • Carcinoma in-situ of the Oral Mucosa has a Definite Tendency towards Keratinization

    Syafriadi Mei, Ida-Yanemochi Hiroko, Ikarashi Terue, Maruyama Satoshi, Jen Kai Yu, Cheng Jun, Hoshina Hideyuki, Takagi Ritsuo, Saku Takashi

    Oral medicine & pathology   8 ( 2 )   43 - 44   2003

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    A 81-year-old female had suffered from a white lesion in the right lateral margin of the tongue for 10 years. The lesions was surgically removed and examined histopathologically. The surgical specimen showed small foci of squamous cell carcinoma invading up to 4 mm in the muscle layer with a diameter of less than 7 mm in the central portion. The carcinomatous foci were surrounded by epithelial dysplasia in various degrees with a dense lymphocytic infiltration in the lamina propriae. Some of the dysplasia parts just next to the carcinomatous foci contained obviously atypical cells without basal cell alignment but with an apparent keratinizing tendency, which could not be otherwise diagnosed as carcinoma in-situ. Based on this case report, a new concept of carcinoma in-situ of the oral mucosa was proposed, because the histology was different in terms of keratinization degree from so-called carcinoma in-situ as frequently seen in the cervix uteri, which were mainly composed of proliferation of basaloid cells.

    DOI： 10.3353/omp.8.43

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    Other Link： http://search.jamas.or.jp/link/ui/2004123235

  • 41. Tumor of the lower lip

    Wael S, Ikarashi T, Ida H, Hoshina H, Takagi R, Koyama J, Hayashi T, Saku T

    Oral medicine & pathology   7 ( 2 )   98 - 98   2002.12

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  • 20. White lesion of the oral mucosa

    Syafriadi M, Ida H, Ikarashi I, Maruyama S, Jen KY, Cheng J, Hoshina H, Takagi R, Saku T

    Oral medicine & pathology   7 ( 2 )   94 - 94   2002.12

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  • マウス歯胚発育過程における基底膜型ヘパラン硫酸プロテオグリカンの局在

    依田 浩子

    歯科基礎医学会雑誌   44 ( 5 )   416 - 416   2002.9

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  • 粘膜下線維症の進行と細胞外基質分子の動態

    宇都宮 宏子, 依田 浩子, 大城 和文, ティラカラトゥネ ワンニンヤケ, 朔 敬

    歯科基礎医学会雑誌   44 ( 5 )   479 - 479   2002.9

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  • Apoptosis is the reason for characteristic two-phase appearance of oral mucosal epithelial dysplasia

    Mei Syafriadi

    Japanese journal of oral biology   44 ( 5 )   496 - 496   2002.9

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  • 口腔扁平上皮癌の遺伝子発現様相に基づくリンパ節転移予測因子の検討

    永田 昌毅, 藤田 一, 依田 浩子, 星名 秀行, 井上 達夫, 長島 克弘, 関 雪絵, 大西 真, 大山 登喜男, 新垣 晋, 朔 敬, 高木 律男

    新潟歯学会雑誌   32 ( 1 )   120 - 120   2002.7

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  • 4 マイクロアレイを用いた遺伝子発現解析に基づく口腔扁平上皮癌の病態と予後因子に関する検討(I. 一般演題)(第 61 回新潟癌治療研究会)

    永田 昌毅, 藤田 一, 星名 秀行, 井上 達夫, 関 雪絵, 高木 律男, 新垣 晋, 依田 浩子, 朔 敬, 大西 真

    Niigata medical journal   116 ( 1 )   50 - 51   2002.1

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    Other Link： http://search.jamas.or.jp/link/ui/2003003825

  • Stromal characteristics of squamous cell carcinoma of the tongue compared between well and poorly-differentiated foci: an immunohistochemical study

    Jen kai Yu

    Japanese journal of oral biology   43 ( 5 )   632 - 632   2001.8

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  • 歯の萌出障害機構の病理学的背景

    Hiroko Ida

    Niigata dental journal   31 ( 1 )   45 - 46   2001.7

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  • 口腔粘膜扁平上皮細胞間基質としての基底膜型ヘパラン硫酸プロテオグリカン

    五十嵐 輝江, 依田 浩子, 木村 信, 朔 敬

    歯科基礎医学会雑誌   42 ( 5 )   442 - 442   2000.8

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  • [第18回] 上顎癌

    Hiroko Ida, Tomoe Nakajyou, Takafumi Hayashi

    Niigata dental journal   30 ( 1 )   65 - 68   2000.7

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    Other Link： http://search.jamas.or.jp/link/ui/2001034633

  • 上唇毛包腫の1例

    Hiroko Utsunomiya, Hiroko Ida, Ichiro Suzuki

    Niigata dental journal   30 ( 1 )   57 - 60   2000.7

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    We report a rare case of a trichofolliculoma of the upper lip in a 48-year-old Japanese man. The tumor, measuring 12×11×11mm in size, was located in the dermis to subcutaneous layer around the mucocutaneous border of his upper lip. There was a small fistula-like pit in the skin covering the tumor. The patient had noticed the tumor for 15 years, during which it grew gradually with occasional excretion of white-colored cheese-like substance from the pit. Its clinical diagnosis was atheroma. Histopathologically, it consisted of a nodular proliferation of fibroblasts with fibrous connective tissues, within which there was a cystic space lined by skin with plentiful dermal appendages. This was the second case report of a labial trichofolliculoma from dental institutions.

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    Other Link： http://search.jamas.or.jp/link/ui/2001031618

  • 骨形成過程における基底膜型ヘパラン硫酸プロテオグリカンの発現

    羽尾 奈津子, 程 君, 木村 信, 依田 浩子, 坂井 英昭, 織田 公光, 高木 律男, 朔 敬

    日本病理学会会誌   89 ( 1 )   332 - 332   2000.3

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  • 唾液腺腺様嚢胞癌における偽嚢胞の成立機序 基底膜関連分子産生担当細胞の同定

    藤森 行彦, 程 君, 木村 信, 依田 浩子, 豊島 公栄, 高木 律男, 朔 敬

    日本病理学会会誌   89 ( 1 )   252 - 252   2000.3

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  • 病的骨新生における基底膜型ヘパラン硫酸プロテオグリカン

    羽尾 奈津子, 依田 浩子, 木村 信, 小林 泰浩, 坂井 英昭, 高木 律男, 織田 公光, 朔 敬

    歯科基礎医学会雑誌   41 ( 5 )   456 - 456   1999.8

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  • マウス歯胚エナメル器における基底膜型ヘパラン硫酸プロテオグリカンの局在

    依田 浩子, 織田 公光, 朔敬

    歯科基礎医学会雑誌   41 ( 5 )   441 - 441   1999.8

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  • Xanthomatous Lesion of the Gingiva : A possible cause of delayed tooth eruption

    Hiroko Ida-Yonemochi, Tadashi Noda, Yukiko Ono, Takashi Saku

    Oral Med. Pathol.   4 ( 2 )   79 - 84   1999

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Presentations

  • 歯胚上皮及び歯髄幹細胞・象牙芽細胞維持に関わる Shh-Ptch-Gli シグナル経路

    石川裕子,依田浩子,斎藤浩太郎,中富満城,大島勇人

    第61回歯科基礎医学会学術大会 

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    Event date： 2019.10

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  • 肥満型 2 型糖尿病モデル TSOD マウスにおける口腔組織の経時的変化

    依田浩子,大島勇人

    第61回歯科基礎医学会学術大会 

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    Event date： 2019.10

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  • 酸素濃度依存的RhoA-actomyosin-YAP/TAZシグナルによるエナメル上皮幹細胞制御機構

    大津圭史,依田浩子,大島勇人,原田英光

    第124回日本解剖学会総会・全国学術集会 

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    Event date： 2019.3

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  • 糖代謝異常がマウス歯髄組織へ及ぼす影響

    依田浩子;大島勇人

    第125回日本解剖学会総会・全国学術集会  2020.3 

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  • Loss of autophagy in chondrocytes causes severe growth retardation.

    Horigome Y, Ida-Yonemochi H, Waguri S, Shibata S, Komatsu M

    Orthopedic Research Society 2020 Annual Meeting  2020.2 

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  • モルモット臼歯における上皮幹細胞ニッチを含む形成端上皮コンパートメントの三次元立体構築

    清野雄多,依田浩子,大島勇人

    令和元年度新潟歯学会第2回例会  2019.11 

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  • Craniofacial abnormality with connective tissue disorder in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-1.

    Ida-Yonemochi H, Morita W, Sugiura N, Kawakami R, Watanabe H, Imamura T, Igarashi M, Ohshima H, Takeuchi K

    11th International Conference on Proteoglycans.  2019.10 

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  • コンドロイチン硫酸合成酵素KOマウスの皮膚と顎顔面異常とコラーゲン発現形成異常

    依田浩子,笹倉寛之,川上良介,今村健志,柴田俊一,大島勇人,武内恒成

    第38回日本糖質学会年会  2019.8 

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  • マウス臼歯切削後の象牙芽細胞再生過程における象牙芽細胞下層の役割

    今井千尋;佐野拓人;斎藤浩太郎;中富満城;依田浩子;岡野栄之;大島勇人

    第124回日本解剖学会総会・全国学術集会  2019.3 

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  • 肥満型糖尿病モデルTSODマウスにおける口腔組織の経時的変化

    依田浩子,監物新一,大島勇人

    第124回日本解剖学会総会・全国学術集会  2019.3 

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  • 歯の形態形成におけるエネルギー代謝調節機構 Invited

    依田 浩子

    第60回歯科基礎医学会学術大会  2018.9 

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  • マウス歯髄発生・再生過程におけるグリコーゲン代謝機構

    依田浩子, 滝澤 舞, 大島勇人

    第123回日本解剖学会総会・全国学術集会  2018.3 

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  • 歯の形成過程におけるAMP-activated protein kinase (AMPK) の発現と機 能

    依田浩子, 大津圭史, 原田英光, 大島勇人

    第59回歯科基礎医学会学術大会  2017.9 

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  • コンドロイチン硫酸は頭蓋顔面形態形成を制御している

    依田浩子, 森田航, 柴田俊一, 大島勇人

    第58回歯科 基礎医学会学術大会  2016.8 

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  • 成熟期エナメル芽細胞の分化制御と糖代謝の役割 Invited

    依田 浩子

    第58回歯科基礎医学会学術大会  2016.8 

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  • Functional significance of sodium-dependent glucose transporters during murine ameloblast differentiation. International conference

    依田 浩子

    12th International Conference on Tooth Morphogenesis and Differentiation (TMD) 2016  2016.6 

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  • エナメル芽細胞分化過程におけるAMP-activated protein kinase (AMPK) の発現と機能

    依田浩子, 大津圭史, 原田英光, 大島勇人

    第122回日本解剖学会総会・全国学術集会  2016.3 

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  • コンドロイチン硫酸合成酵素遺 伝子欠損マウスに生じる顎顔面発育異常

    依田浩子, 森田 航, 柴田俊一, 和田芳野, 五十嵐道弘, 武内恒成, 大島勇人

    第121回日本解剖学会総会・全国学術集会  2016.3 

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Industrial property rights

  • グリコーゲンを含有する骨形成促進剤

    依田 浩子, 大島勇人, 中川英蔵, 田中みか子, 高田洋樹

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    Application no：特願2012-533869 

    Date issued：2016.1

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Awards

  • 令和７年度 新潟大学優秀論文表彰

    2025.8   新潟大学  

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  • 第21回歯科基礎医学会ライオン学術賞

    2021.10  

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  • 令和３年度 新潟大学優秀論文表彰

    2021.8   新潟大学  

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  • 第17回歯科基礎医学会賞

    2005.9  

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Research Projects

  • オートファジーによる歯の幹細胞老化制御メカニズムの解明

    Grant number：24K12867

    2024.4 - 2027.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    依田 浩子, 大島 勇人, 中村 卓史

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • Homeostatic maintenance and activation of dental pulp quiescent stem/progenitor cells regulated by dendritic cells and macrophages

    Grant number：23H03078

    2023.4 - 2026.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

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    Grant amount：\18980000 （ Direct Cost: \14600000 、 Indirect Cost：\4380000 ）

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  • Homeostatic maintenance and activation of dental pulp quiescent stem/progenitor cells regulated by dendritic cells and macrophages

    Grant number：23K27768

    2023.4 - 2026.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

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    Grant amount：\18980000 （ Direct Cost: \14600000 、 Indirect Cost：\4380000 ）

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  • 歯の形成過程における糖代謝リプログラミングの制御機構

    Grant number：21K09826

    2021.4 - 2024.3

    System name：科学研究費助成事業

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    依田 浩子, 入江 太朗, 大島 勇人

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    本課題では歯の形態形成における糖代謝調節機構の包括的理解に向けて、未解明である象牙芽細胞分化、エナメル上皮幹細胞および歯髄幹細胞の動態と糖代謝リプログラミング制御について、オートファジーの関与に焦点を当てて解明することを目的としている。
    エナメル上皮幹細胞動態とオートファジー 制御に関しては、上皮細胞特異的オートファジー不全マウス（Atg7f/f;Keratin14-cre）を用いた解析の結果、加齢に伴いエナメル上皮幹細胞領域であるSox2陽性の切歯形成端の構造が不規則化し、老齢Atg7f/f;Keratin14creマウスでは歯原性腫瘍が発生した。さらに、エナメル上皮細胞株を用いたin vitro実験において、オートファジー阻害によりエナメル上皮幹細胞マーカーであるSox2遺伝子の発現低下と細胞増殖能の低下が確認された。従って、オートファジーが幹細胞性維持に重要であり、その異常が歯原性上皮細胞の腫瘍化に関与している可能性が推察された。
    歯髄組織の発育におけるオートファジーと糖代謝制御に関しては、正常マウス切歯および臼歯の歯髄幹細胞領域にオートファジーマーカーの発現が確認され、歯髄幹細胞性維持にオートファジーが関与している可能性が示唆された。現在、歯髄細胞特異的オートファジー不全マウス（Atg7f/f;Wnt1-cre）を作成中であり、今後は同マウスでの解析を進める予定である。

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  • Clarification of the origin and maintenance mechanisms of junctional epithelium and identification of its stem cells using allogenic tooth germ transplantation

    Grant number：20K21672

    2020.7 - 2022.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    Research category：Grant-in-Aid for Challenging Research (Exploratory)

    Awarding organization：Japan Society for the Promotion of Science

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    Grant amount：\6370000 （ Direct Cost: \4900000 、 Indirect Cost：\1470000 ）

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  • 下顎頭軟骨初期形成を制御する因子の探求

    Grant number：18K06820

    2018.4 - 2021.3

    System name：科学研究費助成事業 基盤研究(C)

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    柴田 俊一, 船戸 紀子, 依田 浩子, 藤川 芳織

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    Grant type：Competitive

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    2018年度はまず研究の骨子として申請書にある「初期下顎頭軟骨形成を制御する候補分子の網羅的検索」を行うため、マイクロアレイ解析を行った。マウス下顎頭軟骨形成に関連するSox9発現前のE13.0日と発現後のE14.0の下顎頭軟骨原基からTotal RNAを抽出し、GeneArray Mouse 2.0STを用いてE14.0で2倍以上発現している遺伝子、1/2以下に減少している遺伝子をそれぞれ同定した。
    ピックアップした遺伝子のうち特に成長因子やそのレセプターに関係するもの、骨、軟骨形成に関与するもの、あるいは細胞外基質成分に相当するものに焦点を当て候補分子の絞り込みを行った。その結果IGFBP famiryの一分子や、カルシトニン関連タンパクあるいはMMP-9等など6分子がE14.0で2倍以上発現している事が明らかとなり、これらを候補遺伝子として次年時以降さらなる解析を行う事とした。
    また候補分子としてもピックアップされたMMP-9を含む数種のMMPおよびそのインヒビターであるTIMP-1,-2,-3の初期下顎頭軟骨形成部位における発現を in situ hybridizationおよびReal Time PCRで検討したところ、MMP-2とTIMP-2が下顎頭軟骨の軟骨膜の外層、MMP-14とTIMP-1はその内層に強く発現する事がわかり、これらの分子が初期化学等軟骨形成に深く関連している事が明らかになった。またMMP-9はおもに破骨細胞に発現が認められ、軟骨形成後のモデリングに関連する事が分かった。これらの結果は大学院生の学位論文として投稿、一部改定後出版された。

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  • Regulatory mechanism of stress-responding glycometabolism in ameloblast differentiation

    Grant number：18K09505

    2018.4 - 2021.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    IDA Hiroko

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    In the process of ameloblast differentiation, the stress markers such as hypoxia and malnutrition were observed in the secretory and maturation stages of ameloblasts. At the same time, autophagy was seen in the papillary layer of the maturation stage. Therefore, the stress was loaded to the ameloblasts during secretion and calcification of enamel matrices, and the stress-responding reaction might be associated with autophagy. In the epithelium-specific autophagy deficient mice, the disorder of enamel formation was observed and it was notably in the hyperglycemic condition. These results suggest that autophagy is involved in the functional maintenance and glucose metabolism of ameloblast-lineage cells in amelogenesis.

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  • Clarification of the homeostatic mechanism and activation of dental pulp progenitor/quiescent stem cells using proteomic approach

    Grant number：17H04366

    2017.4 - 2020.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    Ohshima Hayato

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    Grant type：Competitive

    Grant amount：\17030000 （ Direct Cost: \13100000 、 Indirect Cost：\3930000 ）

    Analysis using TetOP-H2B-GFP mice demonstrated that quiescent stem/progenitor cells resided in the subodontoblastic layer in addition to the perivascular niche in the center of pulp tissue and that the domain of insulin-like growth factor binding protein 5 (IGFBP5) expression was overlapped with this niche. During 3-7 days after autograft, IGFBP5-positve cells were maintained in the dental pulp and lacked a TUNEL-positive reaction, suggesting that IGFBP5 plays a pivotal role in regulating the survival and apoptosis of dental pulp stem cells during both tooth development and pulpal healing following tooth injury. Proteome analysis showed that 156 odontoblast, 183 subodontoblastic, and 76 central pulp tissue layers -specific proteins were identified in molars and that these layers shared 76-988 proteins. The apical bud epithelium and subjacent mesenchyme possessed 258 and 318 tissue-specific proteins, respectively, and shared 1350 proteins in continuously growing incisors.

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  • Mechanisms maintaining quiescent stem cells by Shh signaling in the apical bud of incisors and developing molars in mice

    Grant number：17K11730

    2017.4 - 2020.3

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    Ishikawa Yuko

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    Grant type：Competitive

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    In molars, dense H2B-GFP-label-retaining cells (H2B-GFP-LRCs) were densely distributed throughout the dental pulp during P1 to postnatal week 2 (P2W) and decreased in number by postnatal P3W, whereas the number of dense H2B-GFP-LRCs in the subodontoblastic layer increased in number at P2W. Gli1+ and Ptch1+ cells were distributed throughout the enamel organ and dental pulp, including the odontoblast and subodontoblastic layers. In incisors, the apical bud contained H2B-GFP-LRCs, Gli1+ cells, and Ptch1+ cells. The addition of Shh antibody to explants induced a decrease in the number of Sox2+ cells due to the increase in apoptotic cells in the apical bud.
    Thus, the Shh-Ptch-Gli signaling pathway plays a role in maintaining quiescent adult stem cells and regulating the function of odontoblasts.

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  • Expression and roles of hyaluronan in tooth germ formation

    Grant number：15K11005

    2015.4 - 2018.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    SHIBATA Shunichi

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    Grant type：Competitive

    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    At first, hyaluronan synthase (Has) mRNA expression was investigated in developing mouse tooth germ. As results, Has 2mRNA was detected in mesenchymal tissues around tooth germ. Has3 mRNA was expressed in epithelium including enamel organ, Hertwig's epithelial shoes (HERS), and apical buds of incisor tooth germ.These results indicated that Has 3 is mainly involved in the formation or maintenance of crown and root of tooth germ.
    In order to knock down Has 3 function, siRNA was added to culture media in organ culture system. Compared to control groups, the expression of Has3 was 40% decreased in experimental groups, but no great morphological changes were identified by histological analyzes. Thus function of Has3 for tooth germ formation may be compensated by other molecules such as other types of Has families.

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  • 下顎骨の骨粗鬆症診断：組織から画像へのインタープリテーション

    Grant number：15K11070

    2015.4 - 2016.3

    System name：科学研究費助成事業 基盤研究(C)

    Research category：基盤研究(C)

    Awarding organization：日本学術振興会

    田中 礼, 依田 浩子, 林 孝文, 田中 みか子

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    卵巣摘出後のラットで、骨粗鬆症の下顎骨における病態を明らかにし、組織学的所見と画像所見とを対比させ、組織学的な骨変化が画像にどのように反映されるかを検討することを目的とした。すなわち、下顎骨の経時的な骨吸収形態の観察、骨吸収部での骨代謝の特徴、骨吸収部と骨髄部の組織・細胞の特徴を、形態学的、免疫組織化学的に検討することとした。
    平成27年度は、１）実験動物を用いた研究のための環境整備、２）閉経後骨粗鬆症モデル作成、３）卵巣摘出後３か月および６か月のラットの、(i)軟X線、(ii)マイクロCT、(iii)組織切片、(iv)血清CRPおよびアデｲポネクチン値についてのデータ収集・観察・評価を計画した。
    実際には、環境整備を行い、動物実験倫理委員会の審査承認（5月）を得た。また、卵巣摘出術式の確認および訓練のためラット２頭を購入し、研究分担者２名と術式に沿って実際に卵巣摘出モデルを作成した（6月）。研究代表者に海外転出の可能性が生じたため、動物実験を中断した。その間、Journal of Medical Casesに顎骨壊死の症例を報告し掲載された（９月）。

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  • Elucidation of construction mechanism of extracellular environment around tooth germs via proteoglycan

    Grant number：26462777

    2014.4 - 2017.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    Ida Hiroko, OHSHIMA Hayato

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    Chondroitin sulfate proteoglycan (CSPG) is one of major extracellular matrices and is known to play an important part in organogenesis. To elucidate the role of CS in tooth and craniofacial development and regeneration, we analyzed the craniofacial morphology in chondroitin sulfate synthetic enzyme knockout (CSKO) mice. In normal odontogenesis, the CS chain localized in immature dental papilla and periodontal ligament. In the differentiated dental pulp, CS chain restricted to the apex of tooth root. In CSKO mice, some of KO mice exhibited severe facial developmental defect. Although most of CSKO mice showed normal postnatal development, they exhibited the deformation of cranial bone and malocculusion. These results suggest that CS chain is necessary for normal tooth and craniofacial morphogenesis.

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  • In vivo regulation of chondroitin sulfate gene to recovery from spinal cord injury

    Grant number：26462232

    2014.4 - 2017.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    Takeuchi Kosei, TAMADA Yasushi

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    Grant type：Competitive

    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    Injured adult neurons in the mammalian central nervous system (CNS) rarely regenerate, because some of the intracellular and cell-surface environmental factors inhibit axon regrowth. Chondroitin sulfate (CS) is the most abundant and potent exogenous inhibitor of axonal regeneration. CSGalNAcT1 is a key enzyme in CS biosynthesis. The sponge forms biomaterials impregnated with a mixture containing small molecule compounds or siRNAs was placed on the lesion area in mice suffered neural injuries. The recovery of these mice which treated with drug delivery systems reached the levels of satisfactory amelioration comparable to those of KO mice. Taken together, our results indicated that our drug and delivery system is a promising therapeutic target for treatment of the spinal cord injury and brain infarction, and many treatments of the neural damage.

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  • Involvement of local BDNF after nerve injury in the bone sclerosis change.

    Grant number：25670854

    2013.4 - 2016.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Research category：Grant-in-Aid for Challenging Exploratory Research

    Awarding organization：Japan Society for the Promotion of Science

    KENJI SEO, MAEDA Takeyasu, IDA Hiroko, FUJIWARA Naoshi

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    Grant type：Competitive

    Grant amount：\3770000 （ Direct Cost: \2900000 、 Indirect Cost：\870000 ）

    BDNF is known to promote the natural healing of injured nerves, but it also induces sclerotic changes in bone. We reported that peripheral nerve injury promotes the local production of BDNF. Therefore, this study aimed to evaluate the effect of local BDNF on osteogenesis. Results: BDNF significantly activated the mRNA expression of osteopontin and osteocalcin in MC3T3-E1 cells without affecting cell proliferation. The promotion of the differentiation of MC3T3-E1 cells by BDNF was predicted to occur via the activation of Akt signaling through trkB. Osteopontin-positive new bone formation on the surface of preexisting bone was significantly accelerated in the BDNF-grafted groups, and active bone remodeling, involving osteoblasts, osteoclasts and osteocytes, continued after 28 days due to exogenous BDNF. Conclusion: Local BDNF produced by inferior alveolar nerve injury in the mendible can contribute to accelerating osteosclerotic changes in the alveolar bone.

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  • Subpopulation of dental pulp stem/progenitor cells: Their implication in the differentiation capacity, origin, and microenvironment

    Grant number：25293371

    2013.4 - 2016.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    OHSHIMA Hayato, TSUJIGIWA Hidetsugu, HONDA Masaki, IDA Hiroko, NAKATOMI Mitsushiro, SAITO Kotaro

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    Grant amount：\17550000 （ Direct Cost: \13500000 、 Indirect Cost：\4050000 ）

    Long term label-retaining cells (LRCs) were localized in the subodontoblastic layer as well as the perivascular niche in the center of dental pulp, demonstrated by TetOP-H2B-GFP mutant mice that allow doxycycline-inducible, green fluorescent labeling of cells. The disappearance of LRCs was attributed to the extensive apoptosis occurring significantly in LRCs except for the newly-differentiated odontoblast-like cells even in cases without immunological rejection in the process of pulpal healing following allogenic tooth transplantation. Microarray and immunohistochemical analyses demonstrated that insulin-like growth factor binding protein (IGFBP) 5 is supposed to pay an important role in the maintenance of quiescent dental pulp stem/progenitor cells. Furthermore, the co-localization of transcriptional factor Gli1 and receptor Patched1 in the quiescent stem cells suggests that these cells are regulated by sonic hedgehog signaling.

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  • Elucidation of new function of glycogen - The possibility as accelerating agent for odontogenesis and osteogenesis

    Grant number：24659810

    2012.4 - 2015.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Research category：Grant-in-Aid for Challenging Exploratory Research

    Awarding organization：Japan Society for the Promotion of Science

    IDA Hiroko, TANAKA Mikako, NAKATOMI Mitsushiro, OHSHIMA Hayato

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    Authorship：Principal investigator  Grant type：Competitive

    Grant amount：\3640000 （ Direct Cost: \2800000 、 Indirect Cost：\840000 ）

    Glycogen is a storage form of glucose within mammalian cells and plays a major role in energy metabolism. Temporary glycogen storage has been observed in the cell differentiation stage during organ development, and understanding the glycogen metabolism that underlies various cell dynamics is essential for developing strategies for organ regeneration. Here, we investigated glycogen metabolism in murine tooth development. We demonstrated that glycogen metabolism is an essential pathway for dental cell differentiation. Next, we evaluated the effect of enzymatically synthesized glycogen (ESG) on osteogenesis as well as odontogenesis using in vitro and in vivo experimental model of mice. As results, ESG stimulated the cell growth and differentiation of dental cells and accelerated the growth of tooth explants in vitro. In conclusion, ESG could be a useful stimulant for osteogenesis and odontogenesis.

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  • エナメル器星状網細胞の上皮間葉転換は血管新生の誘導メカニズムになり得るか？

    2012.4 - 2015.3

    System name：挑戦的萌芽研究

    Awarding organization：日本学術振興会

    原田英光

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    Grant type：Competitive

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  • Is epithelial-mesenchymal transition of stellate reticulum cells in enamel organ associated with induction of vasculogenesis?

    Grant number：24659818

    2012.4 - 2014.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    Research category：Grant-in-Aid for Challenging Exploratory Research

    Awarding organization：Japan Society for the Promotion of Science

    HARADA Hidemitsu, HARADA Hidemitsu, IDA Hiroko, OTSU Keishi, ISEKI Sachiko

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    Grant amount：\3640000 （ Direct Cost: \2800000 、 Indirect Cost：\840000 ）

    In the late stage of tooth germ development, vasculogenesis is observed in the enamel organ. To discover the mechanisms of the vasculogenesis, we studied on the relationship between the vasculogenesis and epithelial-mesenchymal transition using Keratin14 cre-b-gal transgenic mouse, Mesp1 cre-b-gal transgenic mouse and Flk1-GFP transgenic mouse. Also, the cell dynamics of enamel organ was observed by real-time imaging of tooth germ organ culture. The study showed that the development of stellate reticulum cells is derived from inner enamel epithelial cells, and that the vasculogenesis and epithelial-mesenchymal transition is closely associated with hypoxia in the enamel organ from expression of Hif1. Furthermore, it is considered that the vasculogenesis is related with ameloblast differentiation to calcify the enamel matrix.

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  • 歯槽骨の骨構造変化を指標とした骨粗鬆症診断法の開発 —歯科臨床からのアプローチ—

    2011.4 - 2015.3

    System name：基盤研究C

    Awarding organization：日本学術振興会

    田中みか子

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    Grant type：Competitive

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  • Development of diagnostic method of osteoporosis using the structural indices of mandibular alveolar bone.

    Grant number：23592839

    2011.4 - 2015.3

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    TANAKA MIKAKO, EJIRI Sadakazu, IDA Hiroko, TANAKA Rei, YAMADA Kazuho, NOMURA Shuichi, SAKURAI Naoki, YAMAMOTO Noriaki, HAYASHI Takafumi, MIKAMI Emi

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    Grant amount：\5200000 （ Direct Cost: \4000000 、 Indirect Cost：\1200000 ）

    The uni-lateral mandibles of ten elderly women were scanned using the dental cone beam CT device. The structural model index (SMI) and the star volume of mandibles showed significant relationships to the calcaneal bone density which was measured using Speed of Sound (SOS) with an ultrasound device. The node number (N.Nd) and the terminus number (N.Tm) as well as the bone surface (BS/TV) (%), trabecular number (Tb.N), and trabecular spacing (Tb. Spac) of mandibles significantly related to one of bone turnover markers, TRACP-5b. The present study therefore revealed changes in alveolar cancellous bone structure of elderly women, and also that this structure varies in relationship to the calcaneal bone density and some of bone turnover markers.

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  • Ｄｕａｌ Ｅｎｅｒｇｙ ＣＴイメージングによる顎骨骨髄微小循環描出の試み

    2011.4 - 2014.3

    System name：基盤研究C

    Awarding organization：日本学術振興会

    田中 礼

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    Grant type：Competitive

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  • Imaging of the microvascular distribution in the mandibular bone marrow using Dual Energy Computed Tomography Imaging; a trial run

    Grant number：23592760

    2011 - 2013

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    TANAKA Ray, HAYASHI Takafumi, IDA Hiroko, IKE Makiko, OHSHIMA Hayato, MARUYAMA Satoshi

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    Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）

    The aim was imaging of the microvascular distribution in the mandibular bone marrow using Dual Energy CT Imaging (DEI). Histopathological specimens of the mandibular bone and pre-operative CT images from the patients who underwent the resection of the mandibular disease were used. The extent of the microvascular distribution within the bone marrow on the histological specimen was subjectively assessed. Multi-Planar Reconstruction Images generated from the pre-operative CT images were compared with the histological findings. Creation of optimal CT images for analysis of the microvascularization in the bone marrow of the mandible was unsatisfactory. The bone marrow area was extremely small to visualize on CT images even with DEI. The area of adipose tissue was predominantly larger than that of microvessels distribution on histological images. It was conceivable that such microvascularization could not make the clear density variations on CT images.

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  • 歯髄再生に関わる歯髄幹細胞と骨髄由来細胞の相互作用の解明と臨床的意義 研究課題

    2010.4 - 2013.3

    System name：基盤研究B

    Awarding organization：日本学術振興会

    大島勇人

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    Grant type：Competitive

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  • Interaction between dental pulp stem cells and bone-marrow-derived cells during pulpal regeneration and its clinical implication

    Grant number：22390341

    2010 - 2012

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    OHSHIMA Hayato, HONDA Masaki, HARADA Hidemitsu, IDA Hiroko, NAKATOMI Mitsushiro, WATANABE Nobukazu, MUTOH Noriko

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    Grant amount：\17030000 （ Direct Cost: \13100000 、 Indirect Cost：\3930000 ）

    Dental pulp stem cells retain proliferative activity and differentiation capacity for odontoblasts during pulpal healing following tooth injuries. Furthermore, donor-host interactions play a crucial role in the reorganization of dental pulp. We succeeded to establish the useful in vitro culture system for the evaluation of the dentin-pulp complex regeneration. These chronological changes in the pulp-dentin border in the in vitro organ culture were similar to the changes in the in vivo experimental models such as tooth replantation/transplantation.

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  • 歯胚エナメル器星状網形成におけるパールカンシグナル伝達機構の解明

    2009.4 - 2012.3

    System name：基盤研究C

    Awarding organization：日本学術振興会

    依田浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • The mechanism of signal transduction of perlecan in the tooth enamel organ morphogenesis

    Grant number：21592321

    2009 - 2011

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    IDA Hiroko, OHSHIMA Hayato, SAKU Takashi

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    Perlecan, a heparan sulfate proteoglycan, plays an important role in cellular growth, differentiation, adhesion and motility by its interaction with growth factors and cytokines. During odontogenesis, perlecan started to be localized in the central area of the epithelial tooth bud, and with the maturation of the enamel organ, it accumulated in the intercellular spaces of the stellate reticulum.
    To understand the role of perlecan in enamel organ morphogenesis, we analyzed a keratin 5-perlecan transgenic mice that over-express perlecan in epithelial cells, and examined their tooth germs. The overexpression of perlecan in the enamel organ resulted in irregular morphology of teeth, suggesting that the expression of perlecan regulates growth factor signaling in a stage-dependent manner during each step of the interaction between ameloblast-lineage cells and mesenchymal cells. The time schedule of the intraepithelial expression of perlecan seems to be controlled critically in the process of odontogenesis.

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  • 東アジア地域における口腔粘膜表在性癌に関する比較分子病理疫学的研究

    2008.4 - 2012.3

    System name：基盤研究B

    Awarding organization：日本学術振興会

    程くん

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    Grant type：Competitive

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  • 外傷歯の歯髄再生療法の基盤となる歯髄細胞の分化誘導法の確立

    2008.4 - 2010.3

    System name：挑戦的萌芽研究

    Awarding organization：日本学術振興会

    大島勇人

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    Grant type：Competitive

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  • Molecular patho-epidemiological study on oral superficial carcinoma in East Asia regions

    Grant number：20406029

    2008 - 2011

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, MARUYAMA Satoshi, SAKU Takashi, IDA Hiroko, YAMAZAKI Manabu

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    Grant amount：\16770000 （ Direct Cost: \12900000 、 Indirect Cost：\3870000 ）

    Oral cancers, especially superficial carcinomas, are increasing in number not only in Japan but also Asian countries, which seems to be in parallel to changing of those countries into aging societies. Epidemiologically and molecular pathologically comparing Japanese cases and East Asian cases, we have shown that oral superficial carcinoma is a lesional complex of borderline malignancies including from epithelial dysplasia to micro-invasive carcinoma by establishing pathological diagnostic criteria for carcinoma in-situ, which were biological evidence-based.

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  • 外傷歯の歯髄再生療法の基盤となる歯髄細胞の分化誘導法の確立

    Grant number：20659296

    2008 - 2009

    System name：科学研究費助成事業 挑戦的萌芽研究

    Research category：挑戦的萌芽研究

    Awarding organization：日本学術振興会

    大島 勇人, 大島 邦子, 重谷 佳見, 依田 浩子, 鈴木 啓展

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    Grant amount：\3200000 （ Direct Cost: \3200000 ）

    【目的】歯の損傷後の歯髄治癒過程における象牙芽細胞分化機構ならびに胎生期ラベリング法によりマウス歯髄組織幹細胞をブロモデオキシウリジン(BrdU)によりラベルし、歯髄におけるBrdU label-retaining cells(LRCs)の分化能を解明することを目的に、歯の移植後の顆粒球マクロファージコロニー刺激因子(GM-CSF)およびオステオポンチン(OPN)の反応、LRCsの分化能を免疫細胞化学的に検索した。
    【方法】妊娠後期ICRマウスに3～4日間BrdUを腹腔内投与し、生後3週後に深麻酔下で上顎第一臼歯抜去後に歯冠部を舌下部へ他家移植した。術後1日～2週後にアルデヒド系固定液で灌流固定し、EDTA脱灰後、パラフィン切片を作製し、抗GM-CSF・抗OPN・抗ネスチン抗体・抗BrdU鼎を用いた免疫染色を行った。なお無処置群の左側臼歯を対照群とした。
    【結果と考察】対照群歯髄では、歯髄中央部血管周囲にLRCsが局在し、咬頭頂領域を中心に歯髄・象牙質界面に弱いオズテオポンチン陽性反応が見られ、象牙芽細胞はネスチン強陽性を示したが、歯髄内はGM-CSFは陰性であった。術後に歯髄のネスチン免疫陽性反応が消失したが、3～7日後に、GM-CSF陽性細胞、OPN陽性細胞の出現に引き続き、ネスチン陽性象牙芽細胞様細胞が歯髄・象牙質界面に再配列した。14日後には歯髄腔に骨組織形成が惹起されたが、骨芽細胞がOPN陽性反応を示した。GM-CSF陽性反応産物は象牙細管内にも見られ、既存の象牙質と再生象牙質の界面にOPN陽性反応が観察された。さらに、in situ hybridizationによりOPN遺伝子発現を検索ると、免疫反応とほぼ同じ発現パターンを示した。また、LRCsは再生象牙芽細胞にコミットされていた。以上より、歯の移植後の歯髄治癒過程における象牙芽細胞の分化には、GM-CSF発現とOPN発現が重要な役割を果たし、LRCsが象牙芽細胞に分化することが明らかとなった。

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  • アジアから東アフリカまで広がる噛みタバコ習慣による口腔がん発症機構

    2007.4 - 2011.3

    System name：海外学術

    Awarding organization：日本学術振興会

    朔 敬

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    Grant type：Competitive

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  • 歯髄組織幹細胞の局在と分化能の解明

    2007.4 - 2010.3

    System name：基盤研究B

    Awarding organization：日本学術振興会

    大島勇人

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    Grant type：Competitive

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  • 口腔粘膜・皮膚の付属器におけるパールカンの役割-上皮過剰発現系マウスによる解析-

    2007.4 - 2009.3

    System name：基盤研究C

    Awarding organization：日本学術振興会

    依田浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • Pathogenesis of oral cancer due to chewing habits spread in Asia to East Africa

    Grant number：19406030

    2007 - 2010

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, CHENG Jun, MARUYAMA Satoshi, IDA Hiroko, YAMAZAKI Manabu

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    Grant amount：\16640000 （ Direct Cost: \12800000 、 Indirect Cost：\3840000 ）

    Since betel quid chewing in the south Asian area is the most representative causative factor of oral cancer, we surveyed oral cancer cases in Yemen, Jordan, Egypt, Sudan, Morocco, and Myanmar, where different sorts of chewing habits are performed. In those areas, chewing-related oral cancer was shown to be one of the most frequent cancers. Analyzing tissue specimens collected from there, we have established important histopathological diagnostic criteria for carcinoma in-situ and epithelial dysplasia both of which superficial carcinoma is comprised of. Their criteria were scientifically supported in multiple aspects by cell biology-based evidence.

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  • Elucidation of the localization and differentiation capacity of dental pulp stem cells

    Grant number：19390462

    2007 - 2009

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    OHSHIMA Hayato, OHSHIMA Kuniko, HONDA Masaki, IDA Hiroko, SUZUKI Hironobu

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    Grant amount：\17420000 （ Direct Cost: \13400000 、 Indirect Cost：\4020000 ）

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  • The role of perlecan in the oral mucosa and the skin appendage-Transgenic mice overexpression of perlecan-

    Grant number：19592105

    2007 - 2008

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    IDA Hiroko

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • 口腔癌細胞浸潤にともなう間質誘導スイッチング機構の分子病理学的解析

    2006.4 - 2009.3

    System name：基盤研究B

    Awarding organization：日本学術振興会

    朔 敬

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    Grant type：Competitive

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  • Molecular and pathology analyses for switching mechanism of stromal inducement in invasive oral carcinoma

    Grant number：18390486

    2006 - 2008

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, CHENG Jun, MARUYAMA Satoshi, SUZUKI Makoto, IDA Hiroko

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    Grant amount：\18450000 （ Direct Cost: \15300000 、 Indirect Cost：\3150000 ）

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  • 上皮組織における基底膜型ヘパラン硫酸プロテオグリカン・パールカンの役割

    2005.4 - 2007.3

    System name：基盤研究C

    Awarding organization：日本学術振興会

    依田 浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • The role of basement membrane type heparan sulfate proteoglycan, perlecan, in epithelial morphogenesis -transgenic mice overexpressing perlecan in the epithelial cells-

    Grant number：17591902

    2005 - 2006

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    IDA Hiroko, MARUYAMA Satoshi, SATOH Toshiya, CHENG Jun, SAKU Takashi, SUZUKI Makoto

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    Grant amount：\3600000 （ Direct Cost: \3600000 ）

    Perlecan, a basement membrane-type heparan sulfate proteoglycan, is localized in the intercellular space of the enamel organ. Hence, it has been suggested to play an important role in tooth morphogenesis. To elucidate the function of perlecan in odontogenesis, we generated transgenic mice overexpressing perlecan in the epithelial cells using a keratin 5 promoter, and examined the effect of perlecan overexpression on enamel organ formation. Transgenic mice were generated by pronuclear microinjection of fertilized C57BL/C3H F1 oocytes with the DNA construct, and they express the entire perlecan core protein under the control of a bovine keratin 5 promoter. Their molar tooth germs were studied by EM, immunohistochemistry, and RT-PCR for perlecan and tooth germ-related molecules.
    Perlecan was immunohistochemically confirmed to be expressed strongly in epithelial tissues, including the enamel organ of Tg mice. Morphologically, the stellate reticulum of the Tg molars showed widened intercellular spaces and thick, irregularly shaped dental laminae at the embryonic stage (E13-E18). In postnatal day 1 (P1) Tg mice, the enamel organ was obviously lacking cell density and was less vascularized. Finally, the crown shape of Tg molars became dull-ended, with incomplete crystallization and divergent tooth roots in mandibular molars. mRNA expression levels for FGF-2, TGF-β1, and PKC-a were elevated in Tg tooth germs at P1.
    From these results, it was suggested that perlecan may control the space arrangement of stromata by binding and releasing of growth factors, and it may act as a carrier for nutrient transport by diffusion within the epithelial milieu. Also in the process of odontogenesis, perlecan might contribute in forming highly hydrated circumstances to realize cell growth and differentiation in the enamel organ. However, the time schedule of the intraepithelial expression of perlecan seems to be critically controlled, because a constant overexpression perlecan has interfered normal tooth morphogenesis.

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  • Molecular biologic and pathologic analysis of Epstein-Barr virus infection related salivary lymphoepithelial carcinoma

    Grant number：16406033

    2004 - 2006

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, MARUYAMA Satoshi, SAKU Takashi

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    Grant amount：\11300000 （ Direct Cost: \11300000 ）

    We have collected the total 180 cases of lymphoepithelial carcinoma (LEC) of salivary gland, which were confirmed as EBV-infected tumors by various molecular biological.
    A complete sequence for the LMP1 gene, one of the EBV gene and has been regarded as an oncogene, was obtained from patients' tissue samples. It was cloned into an expression vector and the constructs were transfected into 293T cells. The transfected cells showed significant elevation of NFkB activities and suppressed cell growth, which were also seen in cells transfected with vectors with different LMP1 genes such as CAO, which has been isolated from a nasopharyngeal carcinoma, and B95-8, a prototype EBV. The results indicated that the expression of LMP1 affects transcription activities in LEC cells but that the overall mutations found in the present study were not always reasons for the tumorigenesis. The promoter region of the LMP1 gene was also analyzed from 20 cases of them, and all of the cases shared common mutational events in regions that were expected to be associated with transcription factors.
    We tried primary cultures for salivary LECs for many times. Unfortunately, however, it was hard to establish cell lines from the cells in culture. In one of the primary cultures, we were successful in maintaining cells, which were confirmed to be their salivary duct epithelial and myoepithelial characteristics as well as EBV infected.
    As a background disease, lymphoepithelial cyst was studied based on clinicopathological analyses of sixty-four cases of the parotid gland. The lymphoid stroma of the cyst seemed to be resulted from granulation tissue reaction of focal sialadenitis but not induced by EBV infection.
    Our functional study shows a new insight for EBV roles in the pathogenesis of salivary LEC, although it is still necessary to carry out further investigations for the whole mechanisms of EBV oncogenesis.

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  • Molecular pathological study of mechanism in malignant changes of oral benign tumors

    Grant number：16591821

    2004 - 2005

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, MARUYAMA Satoshi, SAKU Takeshi

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    Grant amount：\3600000 （ Direct Cost: \3600000 ）

    This research project was carried out in order to study a possible molecular pathway of malignant transformation of oral benign tumors. We mainly focus on salivary pleomorphic adenoma, because we had already proposed a possibility of malignant changes of atypical tumor cells or focal carcinomas within pleomorphic adenomas. To this end, we have isolated six cell systems (designated SMAP1 to SMAP6) from a benign pleomorphic adenoma of the parotid gland of a 61 year-old female. SMAP1/3 showed duct epithelial characteristics with polygonal cell shapes, while SMAP4/6 were spindle-shaped with some myoepithelial cell differentiation. Chromosome analyses showed the cells had not only numeral abnormalities such as 5n ploidies with average numbers of 107 chromosomes but also various kinds of structural abnormalities, such as deletions, translocations, derivatives and isodicentric chromosomes. Among them, der(9)t(9; 13)(p13.3;q12.3) was shared by all of the six cell systems. In addition, they all had a common deletion of the last base G of codon 249 (AGG to AG_) of the p53 gene, which would result in generation of its nonsense gene product. The findings suggest that pleomorphic adenoma contains tumor cells which are precancerous and are able to transform into malignant with above mentioned gene alterations, and the present study is the first in-vitro demonstration that carcinomas can arise secondarily from adenomas in the salivary gland.
    In addition to such gene alterations, there were some other biological characteristics to pleomorphic adenomas. They were capsular and vascular invasions. Their frequency was 100% (extracapular 20%) and 15%, respectively, when examined histopathologically in 104 surgical specimens. In the sites with capsular or vascular invasions, the stroma was myxoid and poorly vascularized. This histology was explained by VEGF and HIF-1a expression modes, which were hypoxia-related. In cells established from a melanotic neuroectodermal tumor of infancy, there was the same chromosome alteration found in SMAP cells, and this translocation will be worthwhile to be investigated further for the molecular mechanism of secondary malignant changes of benign tumors.

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  • 胚エナメル器における基底膜型ヘパラン硫酸プロテオグリカン・パールカンの役割

    2003.4 - 2005.3

    System name：若手研究B

    Awarding organization：日本学術振興会

    依田 浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • Molecular pathological analysis of oral carcinoma caused by chewing habits in Asia

    Grant number：15256005

    2003 - 2006

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    Research category：Grant-in-Aid for Scientific Research (A)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, CHENG Jun, MARUYAMA Satoshi, IDA Hiroko, MIYAZAKI Hideo, NAGAO Toru

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    Grant amount：\34060000 （ Direct Cost: \26200000 、 Indirect Cost：\7860000 ）

    Oral cancers and its precancerous lesions were collected from Taiwan, India, Sri-Lanka, Bangladesh, Yemen, Madagascar, and Myanmar. Through the present collection of oral cancers and precancerous lesions, we have found lesions referred to as superficial carcinoma with or without the custom of chewing tobacco. The frequencies of oral carcinoma were shown to be related to chewing habits. The clinicopathological summary of superficial carcinoma in Japan was characterized by elder female patients, more commonly occurring in the tongue and gingival, less consumptions of tobacco for smoking and alcohol, but association with prosthetic treatments. In contrast, the lesion from Asian countries was found exclusively in the buccal mucosa and gingival, and the patients were mainly males with chewing habits. Histopathology of the superficial carcinoma of the Japanese and Asian patients resembled each other. They were commonly composed of carcinoma in-situ, which could be divided into three types, such as basaloid, verrucous, and acanthotic, and of surrounding epithelial dysplasia with the characteristic two-phase appearances. In addition, intraepithelial deposition of perlecan was demonstrated in epithelial dysplasia and carcinoma in-situ. This finding has been developed into a new concept of intraepithelial stroma. These two findings had greatly contributed to an objective histopathlogical diagnosis for oral borderline malignancies.
    Using paraffin-embedded specimens collected from Asian countries, oral submucous fibrosis and superficial carcinomas were investigated in by immunohistochemistry and in-situ hybridization, PCR, and DNA sequencing techniques. Histopathologically, oral submucous fibrosis was graded with immunohistochemical patterns of extracellular matrix remodeling. The final status of oral submucous fibrosis was also shown to be poorly vascularized or hypoxic, which were important background for oral carcinogenesis. DNA samples obtained by microdissection were analyzed for mutational events in cancer-related genes. Among them, there were several characteristic mutations in the p53 gene which were shared by the collected cases, although samples from Asian countries were not always appropriate for DNA extraction and following experiments.
    Samples of chewing staffs, such as betel, areca nuts, or qat, were organic-chemically demonstrated to have basically the same ingredients from area to area.
    The data obtained in this study showed that oral carcinomas caused by different environmental factors shared similar genetic alterations and histopathological characteristics.

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  • Molecular pathological analysis of intraepithelial distribution of extracellular matrix molecules

    Grant number：15591993

    2003 - 2004

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    SUZUKI Makoto, CHENG Jun, IDA Hiroko, OHSHIRO Kazufumi, SAKU Takashi

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    Extracellular matrix(ECM) has been believed that it is localized in the tissue interstitium and major constituents of the connective tissue. However, based on our previous findings that ECM is also produced by epithelial tumor cells and that tumor cell foci of ameloblastoma which show stellate reticulum-like appearances contained perlecan, one of the major basement membrane molecules, we planned to study intraepithelial localization of ECM in the oral mucosa or enamel organ of the tooth germ.
    In the oral mucosa, perlecan and some other ECM molecules were localized in the parabasal layer of the epithelium. They were enhanced in epithelial dysplasia and carcinoma in-situ but decreased in invasive squamous cell carcinoma in which ECM molecules were mainly localized in the stromal space. The results indicated that perlecan or ECM molecules are required by epithelial cells when they proliferate. Loss of intercellular adherence, one of the important histological characteristics of epithelial dysplasia, has been explained by the enhanced intraepithelial and intercellular deposit of ECM molecules.
    In the tooth germ, perlecan was shown distributed within the expanded intercellular space of stellate reticulum of the enamel organ. The enamel organ cells in the culture also produced perlecan in vitro and in vivo in both protein and mRNA levels. Perlecan was also enriched in the junctional epithelium of the gingival. These results suggest that intraepithelial perlecan functions as one of the substrates which mediate soluble nutrients or intraepithelial migrating cells, such as lymphocytes.
    Based on the results above mentioned, we investigated the productivity of ECM molecules by lymphocytes. Peripheral lymphocytes, when stimulated with mitogens, were shown to be able to produce perlecan and some other ECM molecules and to be immunolocalized on their cell surface. The result suggests that lymphocytes are able to migrate on ECM molecules due to their cell surface integrins, and that the intraepithelial migration of lymphocytes can be realized by mediated by ECM recognition.
    The result obtained in this project has opened new insights in research efforts on epithelial tissues, especial oral and odontogenic ones based on the concept of intraepithelial stroma as well as on the molecular mechanism of cellular migration.

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  • 免疫担当細胞による細胞外基質分子の生合成とその意義-リンパ球・マクロファージの遊走機構基盤と間質改造現象への貢献-

    Grant number：15659434

    2003 - 2004

    System name：科学研究費助成事業 萌芽研究

    Research category：萌芽研究

    Awarding organization：日本学術振興会

    朔 敬, 程 くん, 依田 浩子, 大城 和文

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    1)RT-PCRによる細胞外基質蛋白質の遺伝子発現レベルの検討:培養末梢血リンパ球cDNA試料を、PCR法によって、パールカン、テネイシン、ファイブロネクチン、I・III・IV型コラゲン、ラミニンほか計8種の細胞外基質分子遺伝子を増幅し、アガロースゲル泳動法によって産物を検討した。その結果、PHAほかの活性化刺激によって、正常末梢血リンパ球に細胞外基質分子産生能が誘導されることが判明した。
    2)リンパ球サブタイプにおける細胞外基質分子遺伝子発現:末梢血試料では、T細胞・B細胞に分離して、ECM分子の発現レベルをRT-PCR法と蛍光抗体法で決定したところ、ECM産生細胞は主としてCD3+で、CD4+およびCD8+をふくんでいた。
    3)リンパ球およびマクロファージによる細胞外基質分子産生の蛋白質レベルの検討:培養リンパ球・マクロファージをS35-メチオニンで標識し、上記の各ECM分子とインテグリン各鎖の抗体によって免疫沈降し、SDS-PAGE-フルオログラフィ法または免疫ブロット法で各分子の生合成を経時的に決定したところ、ECM分子は大部分が細胞内に局在し、一部細胞表面に捕捉されていた。
    4)ヒト各種病変におけるリンパ球による細胞外基質発現:ヒト口腔粘膜病変と悪性リンパ腫の病理検査試料をもちいて免疫組織化学法とISH法をおこない、病的環境におけるリンパ球系細胞においてもECM分子の発現されていることを明らかにした。
    5)実験結果評価と研究総括:以上の結果より、リンパ球・マクロファージに細胞外基質産生能があることが明らかになり、遊走ならびに肉芽組織あるいは腫瘍間質の基質合成への関与かの可能性が示唆された。今後は、リンパ球系細胞による細胞外基質産生の機能的な側面を詳細に検討し、免疫機構実現のためのインフラストラクチャを解明していきたい。

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  • 歯胚エナメル器における基底膜型ヘパラン硫酸プロテオグリカン・パールカンの役割

    Grant number：15791038

    2003 - 2004

    System name：科学研究費助成事業 若手研究(B)

    Research category：若手研究(B)

    Awarding organization：日本学術振興会

    依田 浩子

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    Grant amount：\3600000 （ Direct Cost: \3600000 ）

    今年度は、前年度に作製したパールカン上皮細胞過剰発現系トランスジェニックマウス(Tg)の歯胚組織について、とくにエナメル器に着目して組織学的変化を検索した。まず、胎生期から生後の各歯胚発育段階の野生型マウスおよびTg頭部組織のPFA固定パラフィン連続切片を作製し、パールカンおよび各種細胞外基質と増殖因子の免疫組織化学的検索をおこなった。その結果、パールカン蛋白質はケラチン5に一致した局在をしめし、発現鐘状期(胎生18日)のTg臼歯歯胚エナメル器では、歯堤上皮索の肥大と星状網の細胞間隙の拡大が著明で、同部にはパールカンが高度に沈着していた。さらに歯乳頭細胞密度も減少していた。歯冠形成期(生後1日)では、エナメル器内への血管侵入が減少して星状網容積が保持されており、歯冠形態の鈍縁化をきたし、象牙芽細胞の不整列も確認された。したがって、パールカンは歯胚エナメル器細胞の分化と歯冠部形態の誘導に重要な役割をはたし、さらに象牙芽細胞の分化にも関与していることが示唆された。次に、胎生18日、生後1日および生後7日の下顎第一臼歯歯胚組織よりRNAを抽出し、RT-PCR法にて発現遺伝子の差異について検索した。その結果、生後1日齢歯胚において、塩基性線維芽細胞増殖因子(bFGF)、トランスフォーミング成長因子β1(TGF-β1)などの各種増殖因子の軽度発現上昇が確認された。したがって、パールカンはこれら増殖因子を時期特異的に発現調節することによって、歯胚エナメル器の構築ならびに歯胚形成に重要な役割を果たしていることがあきらかとなった(裏面研究発表1,5)。
    以上、前年度および今年度の研究結果より、上皮細胞が産生する細胞外基質分子・パールカンが、歯胚ならびに各種上皮組織(毛、皮膚、唾液腺等)の形態形成や恒常性維持に果たす役割の一部が解明され、今後の再生医療の発展にも新たな研究展望がえられた。

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  • A new anti-cancer strategy by control ling crosstalk of oral carcinoma cells with extracellular matrix molecules

    Grant number：14370581

    2002 - 2004

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, CHENG Jun, IDA Hircko, OHSHIRO Kazufumi, SUZUKI Makoto

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    Grant amount：\15000000 （ Direct Cost: \15000000 ）

    It was poorly understood which cell types, tumor cells or stromal cells, were responsible for the production of extracellular matrix (ECM) molecules in the neoplastic stroma. To investigate the role of each cell type's participation in the production of ECM molecules, as a primary experiment of this research project, the expression of four ECM molecules at the protein and the mRNA levels was studied in two kinds of co-culture systems in direct and indirect contacts between squamous cell carcinoma (SCC) cell systems and stromal fibroblast cell systems. While similar protein and mRNA expression levels for perlecan and other ECM molecules between SCC cells and fibroblasts in a monocellular culture condition, these ECM expression levels of fibroblasts were elevated, and instead those of SCC cells dropped when they were in contact with SCC cells. The differences in the levels between SCC cells and fibroblasts were significantly more evident in direct contact than in indirect contact. These results indicated that oral SCC cells produce ECM molecules in the absence of stromal fibroblasts, which correspond to carcinomas in-situ, and that they stop producing ECM in the presence of fibroblasts, which correspond to invasive SCC. These phenomena were also confirmed in tissue sections from oral carcinoma surgical specimens by immunohistochemistry and in-situ hybridization. In other experiments, ECM production and its metabolism were shown to be controlled by both parenchymal and stromal cells. It is thus suggested that stromal fibroblasts after direct contact with invading SCC cells are more responsible than SCC cells for the formation of neoplastic stroma, and that histological invasion of SCC can be defined as the presence of stromal induction. Based on the findings, we have proposed a tumor biological concept of "parenchymal-stromal switching for ECM production."

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  • Metastasis-associated genes in salivary adenoid cystic carcinoma and oral squamous cell carcinoma : a differential DNA chip analysis between metastatic and non-metastatic cell systems

    Grant number：14571728

    2002 - 2003

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, SAKU Takashi, OHSHIRO Kazufumi, IDA Hiroko, SUZUKI Makoto

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    Overall modes of differential gene expressions were analyzed between human oral/salivary carcinoma cell systems with(MK-1 and ACCM) and without(ZK-1/ZK-2 and ACC2/ACC3) metastatic potential by using micro-array analysis with cancer-associated DNA chips, to determine what kinds of genes were associated with metastatic behaviors. Conspicuous differences in the level of mRNA expression of genes, which are responsible for, cell growth, apoptosis, cytoskeletons, extracellular matrix molecules metabolism, and cellular attachment were commonly shared between ACC2/ACC3 and ACCM or between ZK-1/ZK-2 and MK-1. ACCM and/or MK-1,which have highly metastatic potential, showed lower levels of gene expression in extracellular matrix-related molecules, such as collagens type IV/XVII and laminin, such adhesion molecules as integrins alpha 2/3, cadherin 2,thrombospondin 1/2 and CD44 antigen, but higher levels of genes controlling extracellular matrix degradation, such as MMP 9/15, and cell growth and cell cycle, such as FGF3,FGF7,Sjogren's syndrome/scleroderma autoantigen 1, cyclin dependent kinase 4 and cyclin D1 and adenine phosphoribosyltransferase. The higher protein expression levels for FGF7 in ACCM and lower protein levels for Collagen type IV and laminin were conformed by immunofluorescence. Metastatic potentials of oral/salivary carcinoma cells seem to be resulted from some combinations of over-/under-expression of the genes, which are responsible particularly for cell growth and extracellular matrix metabolism.

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  • Molecularbaological study of craniofacial dysmorphology in transgenic mice bearing Apert type mutant Fgfr2 gene

    Grant number：14370664

    2002 - 2003

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    TAKAGI Rituo, NAGATA Masaki, HOSHINA Hideyuki, SAKU Takashi, FUJITA Hajime, IDA Hiroko

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    Grant amount：\12500000 （ Direct Cost: \12500000 ）

    We surveyed the expression of 557 cancer-related genes in 15 cases of histologically well-differentiated oral squamous cell carcinoma(OSCC) by cDNA microarray analysis. U values and results of SAM(significance analysis of microarray) suggested significance of MMP genes and integrin a3 as the biomarker of lymph node metastasis(LNM). We have collected 140 OSCC samples by collaboration of the four institutes. Real time PCR with TaqMan probes are used for the quantification of gene expression levels in OSCC tissues that were incised at biopsy or operation. We have analyzed the 16 genes of MMPs and MMP inhibitors as the possible clinical biomarkers for the cervical LNM. High expression level of MMP-1,MMP-7,MMP-11 and MMP-13 were significantly correlated with existence of the LNM in the 40 cases of tangue OSCC(20 SCC with LNM and 20 without LNM ; Mann-Whitney test, p<0.05). To identify accurate biomarker system for predicting the risk of lymph node metastasis in OSCC, we further analyzed the expression ratios of MMPs to MMP inhibitors(MMPs/TIMP1 or TIMP2 or RECK). As a consequence, only MMP-1 or MMP-7/TIMP1 or TIMP2 exhibited significance, however, the high level of those expression ratio reflected poor prognosis such as multiple LNM, delayed LNM in small T1 cases, and death by uncontrollable tumor including the case of T1-T4. Whereas gene expression analysis by whole tumor tissue involves biases due to the sampling condition, the consistent clinical significance of MMP-1 and MMP-7 indicates the usefulness of these genes as biomarkers for aggressive characteristics of the OSCC.

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  • アジア民族の表在型口腔粘膜癌の発生に関する病理疫学的研究

    Grant number：14031208

    2002

    System name：科学研究費助成事業 特定領域研究

    Research category：特定領域研究

    Awarding organization：日本学術振興会

    程 クン, 鈴木 誠, 大城 和文, 依田 浩子(米持), 朔 敬

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    わが国(新潟県、本学の病理検査台帳から)500例以上の口腔粘膜癌を抽出し、その中から、前癌病変としての異型上皮をともなう増殖が基本的に表在性に限局される扁平上皮癌46例を検鏡のうえ抽出した。それと同時に、韓国・中国・東南アジア地域のそれぞれの共同研究者に依頼し、各施設から460例の口腔粘膜癌症例が収集した。各国から生検および手術材料のHE染色標本について共同で再検討し、59例が同様の表在性癌に相当する症例として診断を確定した。また、これら症例について、年齢、性、住所、民族、初診時期、口腔診査、症状、経過、処置、予後、とくに歯科補綴処置について、疫学調査を施行した。その結果、従来異型上皮ないしは上皮内癌あるいは初期浸潤癌までを同一病変内に包含する表在性の扁平上皮癌の存在を確認することができた。それらの表在性癌は辺縁部にかならず特徴的な二相性異型上皮をともない、癌部は特徴的な棘細胞型、基底細胞型、疣贅型の三種の組織型に分類できる基本的には上皮内にとどまる扁平上皮癌であった。この病変は、日本人患者の場合、歯科治療歴との密接な関連があり、女性に多いことが特徴的であったが、対照的に東南アジアの患者は、歯科治療歴との関連はなく、噛みたばこ習慣を有し、男性に多いことが判明した。がん抑制遺伝子P53などの免疫組織化学的には、表在性癌と判断される病変内の異なる異型度の上皮内病変は、浸潤性は獲得していないものの、すでに機能的には癌とみなすべき病変であることが示唆された。したがって、口腔粘膜の表在性癌は他臓器とは異なり高分化で従来は診断困難でみのがされてきていることが示唆され、本研究によって口腔粘膜扁平上皮癌の病理組織学的診断基準を新たにする展望がえられた。マイクロディセクション法による遺伝子解析は現在進行中である。

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  • 歯胚発育障害における基底膜型ヘパラン硫酸プロテオグリカンの役割

    2001.4 - 2003.3

    System name：若手研究B

    Awarding organization：日本学術振興会

    依田 浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • Polymorphism in cancer-related genes among oral cancers from the eastern Asian area

    Grant number：13576025

    2001 - 2003

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, OHSHIRO Kazufumi, SUZUKI Makoto, SAKU Takashi, MIYAZAKI Hideo, IDA Hiroko

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    Grant amount：\13500000 （ Direct Cost: \13500000 ）

    Oral cancers and precancerous lesions were collected from China, Sri-Lanka, Bangladesh, and India. Among the present collection of oral cancers and precancerous lesions, we found lesions which can be referred to as superficial carcinoma in many areas with or without the custom of chewing tobacco. There were 128 cases of superficial carcinoma among 800 cases of oral squamous cell carcinoma. Among them, 82 superficial carcinomas out of 680 cases from the Japanese population. The clinicopathobgical characteristics of the Japanese patients with superficial carcinoma were as follows : the patients were mainly older women ; the superficial carcinoma arose more commonly in the longue, gingival, and buccal mucosa ; the Lesions were multiple and recurrent ; less consumptions of tobacco for smoking and alcohol than patients with invasive carcinomas ; the superficial carcinoma lesions had some association with the patients' anamneses for prosthetic treatments. In contrast, the lesion from Asian countries was found exclusively in the buccal mucosa and gingival, and the patients were mainly males with chewing habits. Histopathobgy of the superficial carcinoma was the same among the Japanese and Asian patients. They were commonly composed of carcinoma in-situ, which could be divided into three types, such as basaloid, verrucous, and acanthotic, and of surrounding epithelial dysplasia with the characteristic two-phase appearances. In order to recognize such a disease entity of superficial carcinoma of the oral mucosa, a workshop was taken place in Singapore in August 2002, at which oral pathologists from Japan, Korea, Malaysia, Indonesia, Sri-Lanka, and the United Kingdom attended and discussed about the possibility of the concept
    Using paraffin-embedded specimens collected from Asian countries, superficial carcinomas were investigated in several aspects as follows : the characteristic two-phase appearance in epithelial dysplasia was investigated by immunohistochemistry and in-situ hybridization, and its molecular mechanism was revealed to be due to apoptosis of prickle cells by mechanical stress of basaloid cell proliferation in the lower layer and thick keratinization in the surface layer. In addition, extracellular matrix remodeling in oral submucous fibrosis was determined for one of the backgrounds of oral carcinogenesis. DNA samples obtained by microdissection were analyzed for mutational events in cancer-related genes. Among them, there were several characteristic mutations in the p53 gene which were shared by the collected cases.
    Based on the data obtained in this study, it is highly suggested that superficial carcinomas of the oral mucosa caused by different environmental factors shared similar genetic alterations in the cancer-related genes.

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  • A new anti-cancer strategy by control ling cross talk of oral carcinoma cells with extra cellular matrix molecules

    Grant number：13557157

    2001 - 2003

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, CHENG Jun, IDA Hiroko, OHSHIRO Kazufumi, SUZUKI Makoto, NAKAJIMA Motoo

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    Grant amount：\14100000 （ Direct Cost: \14100000 ）

    In order to study a possibility of anti-cancer effect of inhibition of oral carcinoma cells' cross talk with extracellular matrix molecules, we examined various interactions between oral carcinoma cells and stromal fibroblasts by using cell lines, such as ACC3 or ACCM cells which were derived from human adenoid cystic carcinomas, and ZK-1 or MK-1 cells, which were derived from human squamous cell carcinomas.
    First of all, we examined the effect of suramin, a polysulfonated naphthylurea, on biosyntheses of extracellular matrix (ECM) molecules and their receptor integrins as well as their interaction in ACC3 cells. Suramin enhanced secretion of ECM molecules by ACC3 cells into the culture medium, and it inhibited ACC3 cells to attach in a short-term culture, that was enhanced in the presence of RGD peptides. The molecular mechanism of this phenomenon was proved by our experiments using metabolic labeling, immunoprecipitation, and immunoblotting, RT-PCR, and DNA microarrays. Suramin inhibited the biosynthesis of focal adhesion kinase (FAK) and its assembly into the cell membrane via integrins. At the same time tyrosine phosphorylation of FAK and other molecules were inhibited by suramin, although the gene expression levels for integrins and FAK were not suppressed. The results indicated that enhanced secretion of ECM molecules might result from inability of ACC3 cells to trap them on their cell surface by way of integrins, because integrins failed to be sorted and to be assembled into the cell membrane due to the absence of FAK
    At the same time, the important role of extracellular matrix molecules, especially perlecan, in cellular proliferation was approved in various oral tumor or embryonal cells as well as stromal cells. Perlecan was also shown to be degraded constantly in physical conditions in oral tumor cells, which may indicate that it is metabolized by them for their growth.
    Based on the data obtained in this study, it is highly suggested that oral carcinoma cells require crosstalk with extracellular matrix for their survival and that their proliferation could be suppressed by the inhibition of their recognition of extracellular, matrix.

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  • 歯胚発育障害における基底膜型ヘパラン硫酸プロテオグリカンの役割

    Grant number：13771071

    2001 - 2002

    System name：科学研究費助成事業 若手研究(B)

    Research category：若手研究(B)

    Awarding organization：日本学術振興会

    依田 浩子

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    Grant amount：\2000000 （ Direct Cost: \2000000 ）

    今年度は前年に引き続き、正常歯胚組織の発育過程におけるin vivoでの基底膜型ヘパラン硫酸プロテオグリカン・パールカン(HSPG)の局在を明らかにする目的で,各歯胚発育段階のマウス下顎第一臼歯歯胚(胎生11,13,15,17日齢,生後1,6,10,12,28日齢)について,パラフィン連続切片をもちいて,HSPGコア蛋白質の局在およびHSPG遺伝子発現を免疫組織化学的およびin-situハイブリダイゼーション法にて検索した。その結果,HSPGコア蛋白質は,エナメル器および歯乳頭組織に局在し,とくに,エナメル髄星状網細胞の細胞間隙にきわめて豊富であった。鐘状期歯胚では,エナメル基質形成開始期に限局して,内エナメル芽細胞の細胞基底側および側面の細胞間隙にHSPG免疫陽性の小胞状拡張が出現し,周囲の内エナメル髄細胞にHSPG遺伝子発現がみられた。同時に,象牙芽細胞にもHSPG遺伝子発現が強く認められた。したがって,HSPGがそれらの細胞分化あるいはエナメル髄内の拡散による物質輸送の担体としてエナメル質・象牙質基質合成に関与している可能性が示唆された(裏面研究発表2-4)。
    また,歯胚組織由来とされるエナメル上皮腫においても,エナメル髄様の腫瘍胞巣内にHSPGが特異的高濃度に局在するとともに,腫瘍胞巣浸潤先端部でとくに遺伝子発現が強調されたので,上皮性腫瘍細胞の増殖や浸潤を制御している可能性が示唆された(研究発表1)。
    ついで,歯胚の各構成細胞でのHSPGコア蛋白質の生合成を確認する目的で,歯小嚢・歯乳頭・エナメル髄細胞の初代培養システムを確立し,蛍光抗体法および免疫沈降法,さらにRT-PCR法によって検討したところ,すべての細胞種においてHSPGの蛋白質およびmRNAレベルでの発現が確認された(研究発表4)。
    最後にHSPGの関与する歯胚発育障害機構を解明する目的で,アンチセンスHSPGオリゴヌクレオチド添加・非添加下にて歯胚器官培養をおこなった。アンチセンス添加群の培養歯胚紐織では,エナメル器の発育および象牙芽細胞分化が不良であることが確認されており,HSPGがエナメル芽細胞および象牙芽細胞分化に重要な役割をはたしていることがin vitroでも明らかになった。

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  • 口腔粘膜上皮層内に細胞外基質は存在するか

    Grant number：13877303

    2001 - 2002

    System name：科学研究費助成事業 萌芽研究

    Research category：萌芽研究

    Awarding organization：日本学術振興会

    朔 敬, 大城 和文, 依田 浩子(米持), 程 くん

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    Grant amount：\1700000 （ Direct Cost: \1700000 ）

    (1)正常口腔粘膜ならびに口腔粘膜異型上皮・扁平上皮癌病変における細胞外基質発現:病理組織学的に上皮の形態を正常、過形成上皮、異型上皮、口腔粘膜癌に区分し、ついで、免疫組織化学とハイブリッド組織化学によって基底膜型ヘパラン硫酸プロテオグリカンを中心に、テネイシン、ファイブロネクチン等の細胞外基質およびヘパラン硫酸鎖の局在と遺伝子発現を検討したところ、各分子が上皮層内に発現していることを確認した。正常では、傍基底細胞層を中心に限局していたのが、異型上皮では基底細胞から棘細胞上層まで発現が広がった。しかし、浸潤性癌胞巣内には発現が減弱して間質優位に発現の場が変換したので、浸潤性を獲得しない段階では間質の誘導が不可能なため腫瘍実質細胞自身が間質としての細胞外基質分子を産生沈着し、物質輸送の担体として供している可能性が示唆された。ヘパラン硫酸鎖は、ヘパラン硫酸プロテオグリカンのパールカンコア蛋白質とは異なり、異型上皮から浸潤癌ではその局在が消失したので、両者が同様な代謝経過をとらないことが判明した。
    (2)口腔粘膜病変におけるヘパラナーゼの発現:上記(1)項でヘパラン硫酸鎖とヘパラン硫酸プロテオグリカンのパールカンコア蛋白質とは異なる代謝経過をとることが判明したので、その機序をさぐるために、ヘパラナーゼの発現を検討したところ、ヘパラナーゼは異型上皮の程度が上昇するのと同期してその発現が亢進したので、上皮細胞自身がヘパラン硫酸プロテオグリカンのヘパラン硫酸鎖を消化してコア蛋白質のみを細胞間に沈着している可能性が明らかとなった。
    (3)リンパ球による細胞外基質発現:ヒト末梢血リンパ球をパーコール法によって分離し、PHA刺激により幼若化させたのちに、PCR法、蛍光抗体法、免役沈降法により、パールカンをはじめとする細胞外基質の発現について各分子の発現を確認しえた。したがって、リンパ球は細胞一般の遊走機構と同様にこれらの細胞外基質をみずから産生してそれを遊走のよりどころとしている可能性がしめされた。昨年までに明らかになった上皮層内の浸潤リンパ球の細胞外基質発現現象を合わせ考察すると、非異型上皮性病変では、上皮内を遊走するリンパ球は基質をみずから産生しながら移動を可能としていることが示唆された。

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  • 歯胚発育障害における基底膜型ヘパラン硫酸プロテオグリカンの役割

    2000.4 - 2001.3

    System name：奨励研究A

    Awarding organization：日本学術振興会

    依田 浩子

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    Authorship：Principal investigator  Grant type：Competitive

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  • Molecular biologic and pathologic study of Epstein-Barr virus infected lymphepithalial carcinomas in salivary gland

    Grant number：12576024

    2000 - 2002

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, SUZUKI Makoto, OUSHIRO Kazufumi, CHENG Jun, IDA Hiroko

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    Grant amount：\15200000 （ Direct Cost: \15200000 ）

    A total 180 cases of salivary gland lymphoepithelial carcinoma (LEC) were col lected from Russia-Asian countries. Their paraffin blocks of surgical materials were obtained for imunohistochemistry, in-situ hybridization and DNA extraction
    Immunohistochemically, about 50% of the cases showed positive signals for LMP1 gene products, and 100% of them had EBER-1 RNA signals in tumor cells' nuclei, which suggested a definite EBV infection among salivary LEC cases. From 40 cases of them, the C-terminus of the LMP1 gene was PCR-amplified and direct-sequenced. The results indicated that there were at least two different strains of EBV harboring in salivary LEC and that there were many mutational events in them including the characteristic 30 by delefion. From 12 cases of them, the complete sequence for, the LMP1 gene were obtained, and many and new mutations in addition to those which were already found in nasapharyngeal LEC. The promoter region of the LMP1 gene was also analyzed from 20 cases of them, and all of the cases shared common mutational events in regions which were expected to be associated with transcription factors
    One of the complete sequence obtained as mentioned above were cloned into an expression vector and the constructs were transfected into 293T cells to determine their effectd on the activation of NFkB pathways as well as cell growth. The transfected cells showed significant elevation of NFkB activities and suppressed cell growth, which were also seen in cells transfected with vectors with nasopharyngeal CAO or prototype B95-8. The results indicated that the expression of LMP1 affects transcritption activities in LEC cells but that the overall mutaions found in the present study were not always reasons for the tumorigenesis
    Primary cultures for salivary LECs were tried many times. However, the cells were hard to maintain. One of them are growing now and they were characterized by immunofluorescence and PCR to be epithelial and EBV infected
    The results obtained as above has given us a new insight for EBV roles in the pathogenesis of salivary LEC. To this end, it is necessary to carry out further investigations on molecular functions of EBV oncogenes

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  • Microarray gene expression analysis for development prognostic factors for oral squamous cell carcinoma

    Grant number：12671929

    2000 - 2001

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    NAGATA Masaki, HOSHINA Hideyuki, SAKU Takashi, TAKAGI Ritsuo, FUJITA Hajime, IDA Hiroko

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    We performed gene expression profiling with 500 of the cancer related genes to develop diagnostic system of oral squamous cell carcinoma (OSCC). To eliminate biases caused by difference between tumors or measurements, we selected increased arid decreased genes in all OSCC cases. Unchangeable decreases were observed in gene expression ratio of Retinoic acid receptor gamma, Keratin family genes, and some molecules of desmosomes components against normal oral mucosa. Regular increases were observed in extracellular matrix (ECM)-degrading enzymes such as MMPs, uPA; ECMs such as Tenascin C and Fibronectin 1; Chemokines or transcription factors, such as MIG, IP-10, STAT1, BIGH3, that were induced by growth factors. Results of a cluster analysis indicated the similarity in gene expression patterns between those genes. The expression profile of cancer related genes in OSCC tissues seemed to reflect loss of epithelial characteristics, activated tissue destruction and formation of the cancer stroma, and disturbed phases in signal transudation systems. Comparison between groups with or without the involvement of lymphnode metastasis revealed significantly increased expression of MMP-1, uPA, CD44, Integrin alpha 3 and Paxillin as well as decreased mRNA levels of CD9 and IGFBP2. To confirm the results of gene expression analysis, we preformed immunohistochemistry for the genes that were suggested to associate with metastatic behavior of OSCCs. MMP-1, MMP-3 and uPA were co-localized extensively in inflammatory cells, endotherial cells and ECM structure, but no localization was indicated in tumor cells. Prominent staining of those gene products were observed on eosinophilic, round shaped mononuclear cells that were associated with degrading of surrounding collagen fibers and capillary structures. These histological findings corroborate the co-regulated expression and cooperative function of those ECM-degrading enzymes that were expected in gene expression analyzes. Striking correlation was demonstrated between MMP-1 mRNA revel and lymph node metastasis (U=0, p=0.001). MMP-1 could be an independent and accurate prognostic factor of lymph node metastasis for OSCC. By identifying commonly regulated and characteristic clusters of coexpressed genes, and by compeering the gene expression data with the extensive clinical data, and then by using immunohistochemistry against a subset of significant genes, surgical specimens with diverse backgrounds can be made accessible to extract valuable genes without prior dissection into components of tumor tissue.

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  • Mutational events of p53 gene in salivary gland tumors

    Grant number：12671766

    2000 - 2001

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    CHENG Jun, IDA-YONEMOCHI Hiroko, SAKU Takashi, OHSHIRO Kazufumi

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    In order to determine mutational events of the p53 tumor suppressor gene in salivary gland tumors, 117 cases of surgical materials of salivary tumors were analyzed by a direct sequencing of PCR products of DNA samples extracted from formalin-fixed paraffin-embedded tissue sections. The samples included 35 cases of lymphoepithelioma, 30 of mucoepidermoid carcinoma, 33 of Warthin tumor and 19 of pleomorphic adenoma. At the same time, cultured cells of adenoid cystic carcinoma were also examined.
    Lymphoepithelioma is an undifferentiated carcinoma with the lymphoid stroma and associated with the Epstein-Barr virus infection. The pathogeneses of mucoepidermoid carcinomas and Warthin tumors have been related to the exposure to ionizing radiation by atomic bomb in Hiroshima and Nagasaki. However, nothing is known about the pathogenesis for other types of salivary gland tumor. The investigation was performed in the background of the so far accumulated information.
    In this study we first examined exons 5-7 of p53 gene with PCR-fluoro-SSCP and then cases with abnormal SSCP profiles were subjected to direct sequencing. The results were compared with immunohistochemical staining patterns for p53 protein. Most conspicuous mutational events of p53 gens were found in exons 5-7 of lymphoepitheliomas, which instead showed scarce p53 protein immunopositivity. These mutational points were highly common among the cases examined. In contrast, no apparent mutational events were detected in pleomorphic adenomas, even in those with atypical cells that showed strong immunoreactions for p53 gene products. Warthin tumors and mucoepidermoid carcinomas often showed several point mutations in exons 5 and 7, which did not effect on amino acid translation so much, which seemed to be resulted from genetic polymorphism of the gene. However, these point mutations were shared by many cases of malignant and benign salivary gland tumors.
    These results suggest that the specific point mutations in exons 5 and 7 of the p53 gene found in the present study are important genetic background for salivary gland tumorigenesis.

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  • 歯胚発育障害における基底膜型ヘパラン硫酸プロテオグリカンの役割

    Grant number：12771080

    2000

    System name：科学研究費助成事業 奨励研究(A)

    Research category：奨励研究(A)

    Awarding organization：日本学術振興会

    依田 浩子

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    Grant amount：\1400000 （ Direct Cost: \1400000 ）

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  • Molecular pathologic study of precancerous lesions of the salivary gland

    Grant number：11671864

    1999 - 2000

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    SUZUKI Makoto, IDA Hiroko, OHSHIRO Kazufumi, CHENG Jun, KIMURA Shin, SAKU Takashi

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    Grant amount：\3700000 （ Direct Cost: \3700000 ）

    To establish a notion of the precancerous lesion of the salivary gland, we screened surgical pathology tissue sections of salivary gland, we came to focus on pleomorphic adenomas in terms of the presence of atypical cells and capsular invasion.
    We studied clinicopathologically the frequency and variation of cellular atypia among tumor cells and immunohistochemically for expression status of p53 gene products as well as proliferating cell nuclear antigen(PCNA)in 101 surgical materials of pleomorphic adenomas. Histopathologically, atypical tumor cells were found in 60% of the cases examined. Their mode of distribution was classified into three groups : focal(6 cases, 6%), which could be identified as focal carcinoma, measuring less than 1 mm in diameter ; sporadic(15 cases, 15%)and singular(30 cases, 30%). These atypical cells were located mainly within sheet-like nests of tumor cells but not in chondroid or fibro-hyaline foci. Immunohistochemically, most of the atypical cells were positive for p53 gene products and PCNA.The results indicated that atypical cells with p53 protein accumulation in their nuclei could be regarded as cells in a precancerous state, and that the foci which include these atypical cells are likely to mature to focal carcinomas and then to an apparent form of carcinoma in pleomorphic adenoma.
    In the next place, we examined capsular invasion of pleomorphic adenomas in the same specimens used in the above experiment. Forms of capsular invasion were divided into three types : I.expansive ; II.focally infiltrative ; III.interruptive. One of the three invasion types was at least found in all of the cases examined. Type III was rarer and tended to appear in the background of type I or type II.The invasion sites with types I and II had a characteristic histology of stellate cells in myxoid stroma Hence, the myxoid stroma, which is poor in vascularity, seemed to be quite fertile in proliferation of tumor cells. However, in the invasion site with type III, there was a solid proliferation of tumor cells with tubule formation. Furthermore, vascular invasion by tumor cells was often observed.
    The results indicate that pleomorphic adenoma should not be regarded as a mere benign tumor but that its semi-malignant or premalignant nature should be stressed.

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  • 唾液腺多形性腺腫の血管に乏しい間質の分子病理学的特性とCT造影性

    Grant number：11877330

    1999

    System name：科学研究費助成事業 萌芽的研究

    Research category：萌芽的研究

    Awarding organization：日本学術振興会

    朔 敬, 林 孝文, 木村 信, 程 くん, 依田 浩子, 開 祐司

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    Grant amount：\2000000 （ Direct Cost: \2000000 ）

    唾液腺多形性腺腫の間質はきわめて多彩であるが、その特徴的な軟骨様・粘液様間質には血管分布が乏しい。その間質の病理組織学的特性と画像診断学上の特性とを対比検討するために以下の実験ならびに臨床データの解析をおこなった。
    唾液腺多形性腺腫70症例、筋上皮腫30症例のフォルマリン固定パラフィン切片とPAP法によってUEA-Iレクチン結合および血管内皮細胞マーカCD31の免疫組織化学的局在から腫瘤の間質および血管分布様式を定量的に対比した。また、軟骨基質の血管新生抑制因子コンドロモデュリン-I(ChM-I)の蛋白質レベルの局在を免疫組織化学的に、遺伝子レベルの発現状況をin-situハイブリダイゼーション(ISH)ならびにRT-PCRによって、腫瘍組織および多形性腺腫由来初代培養細胞について検討した。さらに、高速らせん型CT装置によるCT血管造影像を経時的に撮影し、造影強度計測した。
    この結果、多形性腺腫では、腫瘍の実質細胞によって生合成されたいわゆる軟骨様・粘液様間質は本来の支持組織としての脈管神経をいれた線維性結合組織ではなく、血管分布がきわめて乏しいことが示された。いっぽう、筋上皮腫では、基本的組織構築として、血管豊富な支持組織としての線維性間質が存在し、両腫瘍の血管分布密度には大きな相違があった。これを裏づけるように、多形性腺腫のCT造影は、血管より遅れて開始し、血管消退後もより長く持続し、その造影像は不均一であるのに対し、筋上皮腫は、血管と同調した造影の推移を示した。さらに、多形性腺腫の粘液様あるいは軟骨様間質にはChM-Iが腫瘍細胞とともに基質に局在し、同部の腫瘍細胞にはChM-I遺伝子の発現がみられた。また、多形性腺腫由来の初代培養細胞でも、ChM-Iの発現が蛋白質ならびに遺伝子レベルで確定できた。
    以上の結果より、多形性腺腫の間質には血管新生を抑制する環境があり、乏血管性間質はCT造影性にも反映し、血管分布を多形性腺腫鑑別診断の指標としうることが明らかになった。

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  • Anti-oral cancer strategy by means of inhibition of cellular adhesion to extracellula matrices

    Grant number：10557170

    1998 - 2000

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, SUZUKI Makoto, IDA Hiroko, CHENG Jun, NAKAJIMA Motowo, OHSHIRO Kazufumi

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    Grant amount：\13700000 （ Direct Cost: \13700000 ）

    We have analyzed anti-cancer effect in a situation in which adhesion of oral carcinoma cells to extracellular matrices is inhibited. To this end, suramin, a polysulfonated naphthylurea, which has been used as an anti-trypanosoma reagent but has also known as an inhibitor of lysosomal heparanase, was used for inhibition of adhesion of oral carcinoma cells, such as ACC3 cells of human salivary adenoid cystic carcinoma origin.
    ACC3 cells have been known to biosynthesize excessive amounts of extracellular matrix (ECM) molecules, especially basement membrane-associated molecules, such as heparan sulfate proteoglycan, HSPG/perlecan, and fibronectin. When ACCE cess were cultivated in the presence of 100 ;uM suramin, secretion of ECM molecules by ACC3 cells into the culture medium was enhanced. When 200 fM suramin was added, attachment of ACC3 cells to culture dishes reduced significantly. In the presence of suramin and RGD peptides, which are an ECM recoginition site of integrins, the attachment was two times more inhibited. Thus, it was suggested that suramin affected integrih-dependent cell adhesion. By day 7 of culture in the presence of suramin, ECM molecules were shed more prominently into the culture medium of ACC3 cells. Immunofluorescence showed that ECM molecules and integrins were localized within the cytoplasm but not in the extracellular space or in the cell surface. These results indicated suramin inhibited cell membrane assembly of integrin and consequently trapping of ECM molecules by cell surface integrins.
    Immunoprecipitation and pulse-chase experi-ments showed that suramin inhibited biosynthesis of an unknown molecule with Mr. 120 kDa, which was co-precipitated with integrin a5. Immunoblotting experiments showed that the 120 kDa molecule was focal adhesion kinase (FAK), which functions in phospholylation of integrins. The results indicated that suramin inhibit FAK expression of ACC3 cells, which resulted in integrin function in cellular attachment.
    These results clearly indicate that the inhibition of cell surface receptors for ECM molecules can be one of the strategies for suppression of oral carcinoma cell growth.

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  • A variety of molecular crosstalks between extracellular matrices and their cell surface receptors in oral carcinomas

    Grant number：10470379

    1998 - 2000

    System name：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B).

    Research category：Grant-in-Aid for Scientific Research (B).

    Awarding organization：Japan Society for the Promotion of Science

    SAKU Takashi, YONEMOCHI Hiroko, OHSHIRO Kazufumi, CHENG Jun, KIMURA Shin, ODA Kimimitsu

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    Grant amount：\12700000 （ Direct Cost: \12700000 ）

    We have analyzed biosynthesis of extracellular matrix(ECM)molecules by oral carcinoma cells, such as ACC3 established from a human adenoid cystic carcinoma cells, MK-1 and ZK-1 established from oral squamous cell carcinomas. These carcinoma cells were shown to produce basement membrane-associated molecules, especially basement membrane type heparan sulfate proteoglycan, HSPG/perlecan, and fibronectin, FN.
    These two ECM molecules were different in molecular weight with cell types. We examined the molecular background for the variations in molecular size among them, by using immunoprecipitation of 35S-methionin labeled cells with several combinations of oligosaccharide lyases. ACC3 cells produced high molecular weight HSPG/FN, which were resulted from larger proteins due to alternative splicing and addition of N-and O-linked oligosaccharide chains, although more investigations are necessary for the alternative splicing mechanism for HSPG core protein.
    Similarly, integrins, INTs, receptors for ECM molecules, expressed by these cells were different in size. This was mainly due to oligosaccharide additions. Thus, there was a variety of structures of ECM molecules and their receptors among oral carcinoma cells. Since the molecular sizes were parallel with the attachment ability of the cells, it is suggested that the ECM molecular size, which is varied with carcinoma cell types, regulate the biological nature of them.
    Such a variety of molecular crosstalks between ECM molecules and their receptors should be also reflected to the tissue architecture of oral carcinomas as well as tissue remodeling processes of granulation tissues. We also immunolocalized these molecules in oral neoplastic and inflammatory lesions. In relation to these immunohistochemical experiments, we proposed a guideline for enzymatic pretreatments for ECM molecules in various tissue types.
    These results clearly indicate that the molecular structures of ECM molecules and their receptors vary with cell types and that the molecular variety should be reflected in their clinical courses. However, it is unknown from the present study what regulates such molecular variety and if these varieties are actually functions in human carcinoma tissues in vitro.

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Teaching Experience (researchmap)

Teaching Experience

  • 基礎歯学ｺｰｽﾜｰｸ(顎顔面解剖学ベーシックコースII)

    2021
    Institution name：新潟大学

  • 硬組織形態学演習IIA

    2021
    Institution name：新潟大学

  • 硬組織形態学演習IB

    2021
    Institution name：新潟大学

  • 基礎歯学ｺｰｽﾜｰｸ(顎顔面解剖学ベーシックコースI)

    2021
    Institution name：新潟大学

  • 硬組織形態学演習IIB

    2021
    Institution name：新潟大学

  • 硬組織形態学演習IA

    2021
    Institution name：新潟大学

  • 人体解剖学Ⅱ

    2018
    Institution name：新潟大学

  • 人体解剖学Ⅰ

    2017
    Institution name：新潟大学

  • 硬組織形態学演習ⅡB

    2017
    Institution name：新潟大学

  • 硬組織形態学演習ⅠB

    2017
    Institution name：新潟大学

  • 硬組織形態学演習ⅠA

    2017
    Institution name：新潟大学

  • 硬組織形態学演習ⅡA

    2017
    Institution name：新潟大学

  • 中枢神経学

    2012
    -
    2017
    Institution name：新潟大学

  • 人体のしくみ

    2010
    Institution name：新潟大学

  • 骨筋学

    2010
    -
    2017
    Institution name：新潟大学

  • 神経解剖学

    2010
    -
    2011
    Institution name：新潟大学

  • 人体解剖学実習

    2009
    Institution name：新潟大学

  • 人体発生学

    2009
    Institution name：新潟大学

  • 基礎歯学コースワーク(歯胚研究入門)

    2009
    Institution name：新潟大学

  • 口腔組織発生学

    2009
    Institution name：新潟大学

  • 細胞生物学4

    2009
    Institution name：新潟大学

  • 硬組織微細構築学演習

    2009
    Institution name：新潟大学

  • 基礎科学演習

    2008
    -
    2016
    Institution name：新潟大学

  • 病理学総論

    2008
    Institution name：新潟大学

  • 口腔病理学

    2008
    Institution name：新潟大学

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