Updated on 2025/10/09

写真a

 
HIRASHIMA Masanori
 
Organization
Academic Assembly Institute of Medicine and Dentistry IGAKU KEIRETU Professor
Graduate School of Medical and Dental Sciences Molecular and Cellular Medicine Signal Transduction Research Professor
Title
Professor
Homepage
https://www.med.niigata-u.ac.jp/pha/
External link

Degree

  • 博士（医学） ( 1999.3   京都大学 )

Research Interests

  • embryonic edema

  • development

  • blood vessels

  • lymphatic vessels

  • VEGF

Research Areas

  • Life Science / Pharmacology

  • Life Science / Anatomy

Research History (researchmap)

  • Niigata University   Graduate School of Medical and Dental Sciences   Professor

    2019.1

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  • Kobe University   Graduate School of Medicine   Associate Professor

    2007.9 - 2018.12

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  • Keio University   School of Medicine   Research Assistant

    2004.3 - 2007.8

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  • サミュエル・ルネンフェルド研究所   博士研究員

    1999.11 - 2004.2

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  • Kyoto University   Graduate School of Medicine

    1999.4 - 1999.10

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Research History

  • Niigata University   Graduate School of Medical and Dental Sciences Molecular and Cellular Medicine Signal Transduction Research   Professor

    2019.1

Education

  • 京都大学大学院医学研究科博士課程分子医学系専攻

    1995.4 - 1999.3

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  • Kyoto University   Faculty of Medicine   Department of Medical Science

    1989.4 - 1995.3

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Professional Memberships

  • THE JAPANESE VASCULAR BIOLOGY AND MEDICINE ORGANIZATION

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  • THE JAPANESE SOCIETY OF LYMPHOLOGY

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  • THE JAPANESE PHARMACOLOGICAL SOCIETY

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  • THE JAPANESE SOCIETY ON THROMBOSIS AND HEMOSTASIS

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Papers

  • Dose–response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats Reviewed

    Tomoki Takeda, Shotaro Yamano, Yuko Goto, Shigeyuki Hirai, Yusuke Furukawa, Yoshinori Kikuchi, Kyohei Misumi, Masaaki Suzuki, Kenji Takanobu, Hideki Senoh, Misae Saito, Hitomi Kondo, George Daghlian, Young-Kwon Hong, Yasuhiro Yoshimatsu, Masanori Hirashima, Yoichiro Kobashi, Kenzo Okamoto, Takumi Kishimoto, Yumi Umeda

    Particle and Fibre Toxicology   19 ( 1 )   2022.4

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    Background

    In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose–response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace.

    Methods

    Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m<sup>3</sup> CWAAP-A for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 h, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 h/day for 2 days.

    Results

    CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m<sup>3</sup> and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m<sup>3</sup>. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m<sup>3</sup> CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m<sup>3</sup> was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages.

    Conclusions

    Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m<sup>3</sup> CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.

    DOI： 10.1186/s12989-022-00468-9

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    Other Link： https://link.springer.com/article/10.1186/s12989-022-00468-9/fulltext.html

  • Endothelial-specific depletion of TGF-β signaling affects lymphatic function

    Kunpei Fukasawa, Kako Hanada, Kei Ichikawa, Masanori Hirashima, Takahiro Takagi, Susumu Itoh, Testuro Watabe, Fumiko Itoh

    Inflammation and Regeneration   41 ( 1 )   2021.12

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    <title>Abstract</title><sec>
    <title>Background</title>
    Transforming growth factor (TGF)-β is a multifunctional cytokine involved in cell differentiation, cell proliferation, and tissue homeostasis. Although TGF-β signaling is essential for maintaining blood vessel functions, little is known about the role of TGF-β in lymphatic homeostasis.


    </sec><sec>
    <title>Methods</title>
    To delineate the role of TGF-β signaling in lymphatic vessels, TβRII<sup>fl/fl</sup> mice were crossed with Prox1-Cre<sup>ERT2</sup> mice to generate TβRII<sup>fl/fl</sup>; Prox1-Cre<sup>ERT2</sup> mice. The <italic>TβRII</italic> gene in the lymphatic endothelial cells (LECs) of the conditional knockout TβRII<sup>iΔLEC</sup> mice was selectively deleted using tamoxifen. The effects of <italic>TβRII</italic> gene deletion on embryonic lymphangiogenesis, postnatal lymphatic structure and drainage function, tumor lymphangiogenesis, and lymphatic tumor metastasis were investigated.


    </sec><sec>
    <title>Results</title>
    Deficiency of LEC-specific TGF-β signaling in embryos, where lymphangiogenesis is active, caused dorsal edema with dilated lymphatic vessels at E13.5. Postnatal mice in which lymphatic vessels had already been formed displayed dilation and increased bifurcator of lymphatic vessels after tamoxifen administration. Similar dilation was also observed in tumor lymphatic vessels. The drainage of FITC-dextran, which was subcutaneously injected into the soles of the feet of the mice, was reduced in TβRII<sup>iΔLEC</sup> mice. Furthermore, Lewis lung carcinoma cells constitutively expressing GFP (LLC-GFP) transplanted into the footpads of the mice showed reduced patellar lymph node metastasis.


    </sec><sec>
    <title>Conclusion</title>
    These data suggest that TGF-β signaling in LECs maintains the structure of lymphatic vessels and lymphatic homeostasis, in addition to promoting tumor lymphatic metastasis. Therefore, suppression of TGF-β signaling in LECs might be effective in inhibiting cancer metastasis.


    </sec>

    DOI： 10.1186/s41232-021-00185-4

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    Other Link： https://link.springer.com/article/10.1186/s41232-021-00185-4/fulltext.html

  • Roles of Thromboxane Receptor Signaling in Enhancement of Lipopolysaccharide-Induced Lymphangiogenesis and Lymphatic Drainage Function in Diaphragm. Reviewed International journal

    Hiromi Matsuda, Yoshiya Ito, Kanako Hosono, Seri Tsuru, Tomoyoshi Inoue, Shuji Nakamoto, Chie Kurashige, Masanori Hirashima, Shuh Narumiya, Hirotsugu Okamoto, Masataka Majima

    Arteriosclerosis, thrombosis, and vascular biology   41 ( 4 )   1390 - 1407   2021.4

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    [Figure: see text].

    DOI： 10.1161/ATVBAHA.120.315507

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  • MAGIs regulate aPKC to enable balanced distribution of intercellular tension for epithelial sheet homeostasis. Reviewed International journal

    Kenji Matsuzawa, Hayato Ohga, Kenta Shigetomi, Tomohiro Shiiya, Masanori Hirashima, Junichi Ikenouchi

    Communications biology   4 ( 1 )   337 - 337   2021.3

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    Constriction of the apical plasma membrane is a hallmark of epithelial cells that underlies cell shape changes in tissue morphogenesis and maintenance of tissue integrity in homeostasis. Contractile force is exerted by a cortical actomyosin network that is anchored to the plasma membrane by the apical junctional complexes (AJC). In this study, we present evidence that MAGI proteins, structural components of AJC whose function remained unclear, regulate apical constriction of epithelial cells through the Par polarity proteins. We reveal that MAGIs are required to uniformly distribute Partitioning defective-3 (Par-3) at AJC of cells throughout the epithelial monolayer. MAGIs recruit ankyrin-repeat-, SH3-domain- and proline-rich-region-containing protein 2 (ASPP2) to AJC, which modulates Par-3-aPKC to antagonize ROCK-driven contractility. By coupling the adhesion machinery to the polarity proteins to regulate cellular contractility, we propose that MAGIs play essential and central roles in maintaining steady state intercellular tension throughout the epithelial cell sheet.

    DOI： 10.1038/s42003-021-01874-z

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  • Only plantar lesion of punctate palmoplantar keratoderma with a novel missense mutation in the AAGAB gene: Two Japanese familial case reports and review of reported mutations International journal

    Hasegawa, Akito, Hayashi, Ryota, Shimomura, Yutaka, Hirashima, Masanori, Abe, Riichiro

    The Journal of Dermatology   48 ( 12 )   1926 - 1930   2021

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    DOI： 10.1111/1346-8138.16162

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  • Blood and lymphatic systems are segregated by the FLCN tumor suppressor. Reviewed International journal

    Ikue Tai-Nagara, Yukiko Hasumi, Dai Kusumoto, Hisashi Hasumi, Keisuke Okabe, Tomofumi Ando, Fumio Matsuzaki, Fumiko Itoh, Hideyuki Saya, Chang Liu, Wenling Li, Yoh-Suke Mukouyama, W Marston Linehan, Xinyi Liu, Masanori Hirashima, Yutaka Suzuki, Shintaro Funasaki, Yorifumi Satou, Mitsuko Furuya, Masaya Baba, Yoshiaki Kubota

    Nature communications   11 ( 1 )   6314 - 6314   2020.12

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    Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.

    DOI： 10.1038/s41467-020-20156-6

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  • PROX1 Is Associated with Cancer Progression and Prognosis in Gastric Cancer Reviewed

    Masanori Hirashima

    Anticancer Research   38 ( 11 )   6139 - 6145   2018.11

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    DOI： 10.21873/ANTICANRES.12966

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  • Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction. Reviewed International journal

    Nagaharu Tsukiji, Osamu Inoue, Mitsuru Morimoto, Norifumi Tatsumi, Hiroaki Nagatomo, Koji Ueta, Toshiaki Shirai, Tomoyuki Sasaki, Shimon Otake, Shogo Tamura, Toshiaki Tachibana, Masataka Okabe, Masanori Hirashima, Yukio Ozaki, Katsue Suzuki-Inoue

    Blood   132 ( 11 )   1167 - 1179   2018.9

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    Platelets participate in not only thrombosis and hemostasis but also other pathophysiological processes, including tumor metastasis and inflammation. However, the putative role of platelets in the development of solid organs has not yet been described. Here, we report that platelets regulate lung development through the interaction between the platelet-activation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by Clec1b), and its ligand, podoplanin, a membrane protein. Clec-2 deletion in mouse platelets led to lung malformation, which caused respiratory failure and neonatal lethality. In these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent in the primary alveolar septa, which resulted in loss of alveolar elastic fibers and lung malformation. Our data suggest that the lack of adMYFs is caused by abnormal differentiation of lung mesothelial cells (luMCs), the major progenitor of adMYFs. In the developing lung, podoplanin expression is detected in alveolar epithelial cells (AECs), luMCs, and lymphatic endothelial cells (LECs). LEC-specific podoplanin knockout mice showed neonatal lethality and Clec1b-/--like lung developmental abnormalities. Notably, these Clec1b-/--like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-β depletion in fetuses. We propose that the interaction between Clec-2 on platelets and podoplanin on LECs stimulates adMYF differentiation of luMCs through transforming growth factor-β signaling, thus regulating normal lung development.

    DOI： 10.1182/blood-2017-12-823369

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  • VEGFR2 promotes central endothelial activation and the spread of pain in inflammatory arthritis Reviewed

    Nicholas Beazley-Long, Catherine Elizabeth Moss, William Robert Ashby, Samuel Marcus Bestall, Fatimah Almahasneh, Alexandra Margaret Durrant, Andrew Vaughan Benest, Zoe Blackley, Kurt Ballmer-Hofer, Masanori Hirashima, Richard Phillip Hulse, David Owen Bates, Lucy Frances Donaldson

    Brain, Behavior, and Immunity   74   49 - 67   2018

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

    DOI： 10.1016/j.bbi.2018.03.012

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  • Dynamics of angiogenesis in ischemic areas of the infarcted heart Reviewed

    Koichi Kobayashi, Kengo Maeda, Mikito Takefuji, Ryosuke Kikuchi, Yoshihiro Morishita, Masanori Hirashima, Toyoaki Murohara

    SCIENTIFIC REPORTS   7 ( 1 )   7156   2017.8

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    DOI： 10.1038/s41598-017-07524-x

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  • VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis Reviewed

    Jeon Yeob Jang, Sung Yong Choi, Intae Park, Do Young Park, Kibaek Choe, Pilhan Kim, Young Keum Kim, Byung-Joo Lee, Masanori Hirashima, Yoshiaki Kubota, Jeong-Won Park, Sheue-Yann Cheng, Andras Nagy, Young Joo Park, Kari Alitalo, Minho Shong, Gou Young Koh

    EMBO MOLECULAR MEDICINE   9 ( 6 )   750 - 769   2017.6

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    DOI： 10.15252/emmm.201607341

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  • Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown. Reviewed International journal

    Shuntaro Ogura, Kaori Kurata, Yuki Hattori, Hiroshi Takase, Toshina Ishiguro-Oonuma, Yoonha Hwang, Soyeon Ahn, Inwon Park, Wataru Ikeda, Sentaro Kusuhara, Yoko Fukushima, Hiromi Nara, Hideto Sakai, Takashi Fujiwara, Jun Matsushita, Masatsugu Ema, Masanori Hirashima, Takashi Minami, Masabumi Shibuya, Nobuyuki Takakura, Pilhan Kim, Takaki Miyata, Yuichiro Ogura, Akiyoshi Uemura

    JCI insight   2 ( 3 )   e90905   2017.2

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    In the central nervous system, endothelial cells (ECs) and pericytes (PCs) of blood vessel walls cooperatively form a physical and chemical barrier to maintain neural homeostasis. However, in diabetic retinopathy (DR), the loss of PCs from vessel walls is assumed to cause breakdown of the blood-retina barrier (BRB) and subsequent vision-threatening vascular dysfunctions. Nonetheless, the lack of adequate DR animal models has precluded disease understanding and drug discovery. Here, by using an anti-PDGFRβ antibody, we show that transient inhibition of the PC recruitment to developing retinal vessels sustained EC-PC dissociations and BRB breakdown in adult mouse retinas, reproducing characteristic features of DR such as hyperpermeability, hypoperfusion, and neoangiogenesis. Notably, PC depletion directly induced inflammatory responses in ECs and perivascular infiltration of macrophages, whereby macrophage-derived VEGF and placental growth factor (PlGF) activated VEGFR1 in macrophages and VEGFR2 in ECs. Moreover, angiopoietin-2 (Angpt2) upregulation and Tie1 downregulation activated FOXO1 in PC-free ECs locally at the leaky aneurysms. This cycle of vessel damage was shut down by simultaneously blocking VEGF, PlGF, and Angpt2, thus restoring the BRB integrity. Together, our model provides new opportunities for identifying the sequential events triggered by PC deficiency, not only in DR, but also in various neurological disorders.

    DOI： 10.1172/jci.insight.90905

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  • PKN2 is essential for mouse embryonic development and proliferation of mouse fibroblasts Reviewed

    Sally Danno, Koji Kubouchi, Mona Mehruba, Manabu Abe, Rie Natsume, Kenji Sakimura, Satoshi Eguchi, Masahiro Oka, Masanori Hirashima, Hiroki Yasuda, Hideyuki Mukai

    GENES TO CELLS   22 ( 2 )   220 - 236   2017.2

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    DOI： 10.1111/gtc.12470

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  • Semaphorin 3G Provides a Repulsive Guidance Cue to Lymphatic Endothelial Cells via Neuropilin-2/PlexinD1 Reviewed

    Xinyi Liu, Akiyoshi Uemura, Yoko Fukushima, Yutaka Yoshida, Masanori Hirashima

    CELL REPORTS   17 ( 9 )   2299 - 2311   2016.11

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    DOI： 10.1016/j.celrep.2016.11.008

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  • Flt1/VEGFR1 heterozygosity causes transient embryonic edema Reviewed

    Yasunori Otowa, Kazumasa Moriwaki, Keigo Sano, Masanori Shirakabe, Shigenobu Yonemura, Masabumi Shibuya, Janet Rossant, Toshio Suda, Yoshihiro Kakeji, Masanori Hirashima

    SCIENTIFIC REPORTS   6   27186   2016.6

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    DOI： 10.1038/srep27186

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  • An Adaptor Molecule Afadin Regulates Lymphangiogenesis by Modulating RhoA Activity in the Developing Mouse Embryo Reviewed

    Takashi Majima, Keisuke Takeuchi, Keigo Sano, Masanori Hirashima, Dimitar P. Zankov, Miki Tanaka-Okamoto, Hiroyoshi Ishizaki, Jun Miyoshi, Hisakazu Ogita

    PLoS ONE   8 ( 6 )   e68134   2013.6

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    DOI： 10.1371/journal.pone.0068134

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  • EphrinB2-EphB4 Signals Regulate Formation and Maintenance of Funnel-Shaped Valves in Corneal Lymphatic Capillaries Reviewed

    Hideto Katsuta, Yoko Fukushima, Kazuichi Maruyama, Masanori Hirashima, Kohji Nishida, Shin-Ichi Nishikawa, Akiyoshi Uemura

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE   54 ( 6 )   4102 - 4108   2013.6

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    DOI： 10.1167/iovs.12-11436

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  • Enhanced Angpt1/Tie2 signaling affects the differentiation and long-term repopulation ability of hematopoietic stem cells Reviewed

    Yoshiko Matsumoto Ikushima, Fumio Arai, Yuka Nakamura, Kentaro Hosokawa, Yoshiaki Kubota, Masanori Hirashima, Hirofumi Toyama, Toshio Suda

    Biochemical and Biophysical Research Communications   430 ( 1 )   20 - 25   2013.1

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    DOI： 10.1016/j.bbrc.2012.11.002

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  • [VEGF receptors]. Reviewed

    Sano K, Hirashima M

    Nihon rinsho. Japanese journal of clinical medicine   70 Suppl 8   31 - 35   2012.11

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  • Arhgef15 Promotes Retinal Angiogenesis by Mediating VEGF-Induced Cdc42 Activation and Potentiating RhoJ Inactivation in Endothelial Cells Reviewed

    Sentaro Kusuhara, Yoko Fukushima, Shigetomo Fukuhara, Lars Martin Jakt, Mitsuhiro Okada, Yuri Shimizu, Masayuki Hata, Kohji Nishida, Akira Negi, Masanori Hirashima, Naoki Mochizuki, Shin-Ichi Nishikawa, Akiyoshi Uemura

    PLOS ONE   7 ( 9 )   e45858   2012.9

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    DOI： 10.1371/journal.pone.0045858

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  • Platelet Activation Receptor CLEC-2 Regulates Blood/Lymphatic Vessel Separation by Inhibiting Proliferation, Migration, and Tube Formation of Lymphatic Endothelial Cells Reviewed

    Makoto Osada, Osamu Inoue, Guo Ding, Toshiaki Shirai, Hirotake Ichise, Kazuyoshi Hirayama, Katsuhiro Takano, Yutaka Yatomi, Masanori Hirashima, Hideki Fujii, Katsue Suzuki-Inoue, Yukio Ozaki

    JOURNAL OF BIOLOGICAL CHEMISTRY   287 ( 26 )   22241 - 22252   2012.6

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    DOI： 10.1074/jbc.M111.329987

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  • Flt1 and Flk1 mediate regulation of intraocular pressure and their double heterozygosity causes the buphthalmia in mice Reviewed

    Keigo Sano, Osamu Katsuta, Satoshi Shirae, Yoshiaki Kubota, Masatsugu Ema, Toshio Suda, Masatsugu Nakamura, Masanori Hirashima

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   420 ( 2 )   422 - 427   2012.4

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    DOI： 10.1016/j.bbrc.2012.03.011

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  • The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice Reviewed

    Shigetomo Fukuhara, Szandor Simmons, Shunsuke Kawamura, Asuka Inoue, Yasuko Orba, Takeshi Tokudome, Yuji Sunden, Yuji Arai, Kazumasa Moriwaki, Junji Ishida, Akiyoshi Uemura, Hiroshi Kiyonari, Takaya Abe, Akiyoshi Fukamizu, Masanori Hirashima, Hirofumi Sawa, Junken Aoki, Masaru Ishii, Naoki Mochizuki

    JOURNAL OF CLINICAL INVESTIGATION   122 ( 4 )   1416 - 1426   2012.4

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    DOI： 10.1172/JCI60746

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  • Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice Reviewed

    Yoko Fukushima, Mitsuhiro Okada, Hiroshi Kataoka, Masanori Hirashima, Yutaka Yoshida, Fanny Mann, Fumi Gomi, Kohji Nishida, Shin-Ichi Nishikawa, Akiyoshi Uemura

    JOURNAL OF CLINICAL INVESTIGATION   121 ( 5 )   1974 - 1985   2011.5

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    DOI： 10.1172/JCI44900

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  • Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero Reviewed

    Yoshiaki Kubota, Keiyo Takubo, Masanori Hirashima, Narihito Nagoshi, Kazuo Kishi, Yuji Okuno, Ayako Nakamura-Ishizu, Keigo Sano, Masato Murakami, Masatsugu Ema, Yoshiki Omatsu, Satoru Takahashi, Takashi Nagasawa, Masabumi Shibuya, Hideyuki Okano, Toshio Suda

    JOURNAL OF EXPERIMENTAL MEDICINE   208 ( 5 )   949 - 960   2011.5

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    DOI： 10.1084/jem.20102187

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  • DOCK180 Is a Rac Activator That Regulates Cardiovascular Development by Acting Downstream of CXCR4 Reviewed

    Fumiyuki Sanematsu, Masanori Hirashima, Melanie Laurin, Ryosuke Takii, Akihiko Nishikimi, Keiko Kitajima, Guo Ding, Mamiko Noda, Yuzo Murata, Yoshihiko Tanaka, Sadahiko Masuko, Toshio Suda, Chikara Meno, Jean-Francois Cote, Takashi Nagasawa, Yoshinori Fukui

    CIRCULATION RESEARCH   107 ( 9 )   1102 - 1105   2010.10

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    DOI： 10.1161/CIRCRESAHA.110.223388

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  • Glomerular Structure and Function Require Paracrine, Not Autocrine, VEGF-VEGFR-2 Signaling Reviewed

    Karen Sison, Vera Eremina, Hans Baelde, Wang Min, Masanori Hirashima, I. George Fantus, Susan E. Quaggin

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   21 ( 10 )   1691 - 1701   2010.10

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    DOI： 10.1681/ASN.2010030295

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  • Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2: Embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets Reviewed

    Katsue Suzuki-Inoue, Osamu Inoue, Guo Ding, Satoshi Nishimura, Kazuya Hokamura, Koji Eto, Hirokazu Kashiwagi, Yoshiaki Tomiyama, Yutaka Yatomi, Kazuo Umemura, Yonchol Shin, Masanori Hirashima, Yukio Ozaki

    JOURNAL OF BIOLOGICAL CHEMISTRY   285 ( 32 )   24494 - 24507   2010.8

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    DOI： 10.1074/jbc.M110.130575

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  • Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis Reviewed

    Kaori Harada, Tomoko Yamazaki, Caname Iwata, Yasuhiro Yoshimatsu, Hitoshi Sase, Koichi Mishima, Yasuyuki Morishita, Masanori Hirashima, Yuichi Oike, Toshio Suda, Naoyuki Miura, Tetsuro Watabe, Kohei Miyazono

    JOURNAL OF CELL SCIENCE   122 ( 21 )   3923 - 3930   2009.11

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    DOI： 10.1242/jcs.052324

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  • Impaired vascular development in the yolk sac and allantois in mice lacking RA-GEF-1 Reviewed

    Hoshimi Kanemura, Takaya Satoh, Shymaa E. Bilasy, Shuji Ueda, Masanori Hirashima, Tohru Kataoka

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   387 ( 4 )   754 - 759   2009.10

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    DOI： 10.1016/j.bbrc.2009.07.108

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  • Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth Reviewed

    Romulo J. C. Albuquerque, Takahiko Hayashi, Won Gil Cho, Mark E. Kleinman, Sami Dridi, Atsunobu Takeda, Judit Z. Baffi, Kiyoshi Yamada, Hiroki Kaneko, Martha G. Green, Joe Chappell, Joerg Wilting, Herbert A. Weich, Satoru Yamagami, Shiro Amano, Nobuhisa Mizuki, Jonathan S. Alexander, Martha L. Peterson, Rolf A. Brekken, Masanori Hirashima, Seema Capoor, Tomohiko Usui, Balamurali K. Ambati, Jayakrishna Ambati

    NATURE MEDICINE   15 ( 9 )   1023 - U74   2009.9

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    DOI： 10.1038/nm.2018

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  • Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli Reviewed

    Rui Benedito, Alexandre Trindade, Masanori Hirashima, Domingos Henrique, Luis Lopes da Costa, Janet Rossant, Parkash S. Gill, Antonio Duarte

    BMC DEVELOPMENTAL BIOLOGY   8   117   2008.12

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    DOI： 10.1186/1471-213X-8-117

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  • Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice Reviewed

    Yoshiaki Kubota, Masanori Hirashima, Kazuo Kishi, Colin L. Stewart, Toshio Suda

    JOURNAL OF CLINICAL INVESTIGATION   118 ( 7 )   2393 - 2403   2008.7

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    DOI： 10.1172/JCI34882

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  • Lymphatic vessel assembly is impaired in Aspp1-deficient mouse embryos Reviewed

    Masanori Hirashima, Keigo Sano, Toru Morisada, Kyoko Murakami, Janet Rossant, Toshio Suda

    DEVELOPMENTAL BIOLOGY   316 ( 1 )   149 - 159   2008.4

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    DOI： 10.1016/j.ydbio.2008.01.023

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  • Ras signaling directs endothelial specification of VEGFR2(+) vascular progenitor cells Reviewed

    Kyoko Kawasaki, Tetsuro Watabe, Hitoshi Sase, Masanori Hirashima, Hiroshi Koide, Yasuyuki Morishita, Keiko Yuki, Toshikuni Sasaoka, Toshio Suda, Motoya Katsuki, Kohei Miyazono, Keiji Miyazawa

    JOURNAL OF CELL BIOLOGY   181 ( 1 )   131 - 141   2008.4

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    DOI： 10.1083/jcb.200709127

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  • VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment Reviewed

    Masato Murakami, Yujuan Zheng, Masanori Hirashima, Toshio Suda, Yohei Morita, Jun Ooehara, Hideo Ema, Guo-Hua Fong, Masabumi Shibuya

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   28 ( 4 )   658 - 664   2008.4

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    DOI： 10.1161/ATVBAHA.107.150433

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  • Prox1 induces lymphatic endothelial differentiation via integrin alpha 9 and other signaling cascades Reviewed

    Koichi Mishima, Tetsuro Watabe, Akira Saito, Yasuhiro Yoshimatsu, Natsuko Imaizumi, Shinji Masui, Masanori Hirashima, Tohru Morisada, Yuichi Oike, Makoto Araie, Hitoshi Niwa, Hajime Kubo, Toshio Suda, Kohei Miyazono

    MOLECULAR BIOLOGY OF THE CELL   18 ( 4 )   1421 - 1429   2007.4

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    DOI： 10.1091/mbc.E06-09-0780

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  • Dosage-sensitive requirement for mouse Dll4 in artery development Reviewed

    A Duarte, M Hirashima, R Benedito, A Trindade, P Diniz, E Bekman, L Costa, D Henrique, J Rossant

    GENES & DEVELOPMENT   18 ( 20 )   2474 - 2478   2004.10

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    DOI： 10.1101/gad.1239004

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  • Gene-trap expression screening to identify endothelial-specific genes Reviewed

    M Hirashima, A Bernstein, WL Stanford, J Rossant

    BLOOD   104 ( 3 )   711 - 718   2004.8

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    DOI： 10.1182/blood-2004-01-0254

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  • Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages Reviewed

    Y Kimura, N Jones, M Kluppel, M Hirashima, K Tachibana, JB Cohn, JL Wrana, T Pawson, A Bernstein

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   101 ( 16 )   6015 - 6020   2004.4

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    DOI： 10.1073/pnas.0305363101

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  • Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal-fetal interface in the mouse placenta Reviewed

    M Hirashima, Y Lu, L Byers, J Rossant

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   100 ( 26 )   15637 - 15642   2003.12

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    DOI： 10.1073/pnas.2635424100

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  • A chemically defined culture of VEGFR2(+) cells derived from embryonic stem cells reveals the role of VEGFR1 in tuning the threshold for VEGF in developing endothelial cells Reviewed

    M Hirashima, M Ogawa, S Nishikawa, K Matsumura, K Kawasaki, M Shibuya, SI Nishikawa

    BLOOD   101 ( 6 )   2261 - 2267   2003.3

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    DOI： 10.1182/blood-2002-01-0003

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  • Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse Reviewed

    M Ema, P Faloon, WL Zhang, M Hirashima, T Reid, WL Stanford, S Orkin, K Choi, J Rossant

    GENES & DEVELOPMENT   17 ( 3 )   380 - 393   2003.2

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    DOI： 10.1101/gad.1049803

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  • Modulation of VEGFR-2-mediated endothelial-cell activity by VEGF-C/VEGFR-3 Reviewed

    K Matsumura, M Hirashima, M Ogawa, H Kubo, H Hisatsune, N Kondo, S Nishikawa, T Chiba, SI Nishikawa

    BLOOD   101 ( 4 )   1367 - 1374   2003.2

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    DOI： 10.1182/blood-2002-05-1329

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  • Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells Reviewed

    A Uemura, M Ogawa, M Hirashima, T Fujiwara, S Koyama, H Takagi, Y Honda, SJ Wiegand, GD Yancopoulos, SI Nishikawa

    JOURNAL OF CLINICAL INVESTIGATION   110 ( 11 )   1619 - 1628   2002.12

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    DOI： 10.1172/JCI200215621

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  • Zinc finger protein, Hzf, is required for megakaryocyte development and hemostasis Reviewed

    Y Kimura, A Hart, M Hirashima, C Wang, D Holmyard, J Pittman, XL Pang, CW Jackson, A Bernstein

    JOURNAL OF EXPERIMENTAL MEDICINE   195 ( 7 )   941 - 952   2002.4

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    DOI： 10.1084/jem.20011522

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  • Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors Reviewed

    J Yamashita, H Itoh, M Hirashima, M Ogawa, S Nishikawa, T Yurugi, M Naito, K Nakao, S Nishikawa

    NATURE   408 ( 6808 )   92 - 96   2000.11

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    DOI： 10.1038/35040568

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  • Maturation of embryonic stem cells into endothelial cells in an in vitro model of vasculogenesis Reviewed

    M Hirashima, H Kataoka, S Nishikawa, N Matsuyoshi, SI Nishikawa

    BLOOD   93 ( 4 )   1253 - 1263   1999.2

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    DOI： 10.1182/blood.V93.4.1253.404k31_1253_1263

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  • Progressive lineage analysis by cell sorting and culture identifies FLK1(+)VE-cadherin(+) cells at a diverging point of endothelial and hemopoietic lineages Reviewed

    S Nishikawa, S Nishikawa, M Hirashima, N Matsuyoshi, H Kodama

    DEVELOPMENT   125 ( 9 )   1747 - 1757   1998.5

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  • Variation of hepatitis B virus precore/core gene sequence in acute and fulminant hepatitis B Reviewed

    TT Aye, T Uchida, SO Becker, M Hirashima, T Shikata, F Komine, M Moriyama, Y Arakawa, S Mima, M Mizokami, JYN Lau

    DIGESTIVE DISEASES AND SCIENCES   39 ( 6 )   1281 - 1287   1994.6

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    DOI： 10.1007/bf02093794

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  • Detection of precore/core-mutant hepatitis B virus (HBV) genome in patients with acute or fulminant hepatitis without serological markers for recent HBV infection Reviewed

    T Uchida, TT Aye, SO Becker, M Hirashima, T Shikata, F Komine, M Moriyama, Y Arakawa, S Takase, S Mima

    JOURNAL OF HEPATOLOGY   18 ( 3 )   369 - 372   1993.7

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    DOI： 10.1016/s0168-8278(05)80283-1

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MISC

  • 内皮間葉移行で促進される上皮間葉移行におけるETSファミリー転写因子の役割

    吉松 康裕, 前田 健太郎, 高橋 直也, 若林 育海, 紀室 志織, 高橋 和樹, 小林 美穂, 井上 カタジナアンナ, 平島 正則, 宮園 浩平, 渡部 徹郎

    日本癌学会総会記事   80回   [E11 - 5]   2021.9

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  • Regulation of endothelial cell differentiation and arterial specification by VEGF and Notch signaling Invited

    Masanori Hirashima

    ANATOMICAL SCIENCE INTERNATIONAL   84 ( 3 )   95 - 101   2009.9

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    DOI： 10.1007/s12565-009-0026-1

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  • Differentiation of arterial and venous endothelial cells and vascular morphogenesis Invited

    M Hirashima, T Suda

    ENDOTHELIUM-JOURNAL OF ENDOTHELIAL CELL RESEARCH   13 ( 2 )   137 - 145   2006.3

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    DOI： 10.1080/10623320600698078

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  • Vascular development and patterning: making the right choices Invited

    J Rossant, M Hirashima

    CURRENT OPINION IN GENETICS & DEVELOPMENT   13 ( 4 )   408 - 412   2003.8

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    DOI： 10.1016/S0959-437X(03)00080-7

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  • Cell biology of vascular endothelial cells Invited

    Masanori Hirashima

    Annals of the New York Academy of Sciences   947   35 - 40   2001.12

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    DOI： 10.1111/J.1749-6632.2001.TB03928.X

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  • Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family Invited

    H Yoshida, N Takakura, M Hirashima, H Kataoka, K Tsuchida, S Nishikawa, S Nishikawa

    DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY   22 ( 3 )   321 - 332   1998.5

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    DOI： 10.1016/s0145-305x(98)00008-1

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Awards

  • 岡本研究奨励賞（第24回）

    2009.9   成人血管病研究振興財団   内皮細胞分化と血管・リンパ管形成に関する研究

    Hirashima Masanori

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  • Best Young Investigator Award

    2006.12   第14回日本血管生物医学会学術集会  

    平島 正則

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Research Projects

  • マイクロサージェリーを用いないリンパ浮腫の外科治療を開発する

    Grant number：24K12843

    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

    田中 宏明, 平島 正則, 松田 健, 椎谷 友博

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

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  • 血小板とリンパ管内皮細胞の相互作用を標的にした新たなリンパ浮腫治療の開発

    Grant number：22K09854

    2022.4 - 2025.3

    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

    植木 春香, 田中 宏明, 平島 正則, 松田 健, 椎谷 友博

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    Grant amount：\4030000 （ Direct Cost: \3100000 、 Indirect Cost：\930000 ）

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  • リンパ管・血管分離を維持する血小板放出因子の作用機序

    Grant number：22K06788

    2022.4 - 2025.3

    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

    椎谷 友博, 平島 正則

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

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  • リンパ節におけるリンパ洞フィルターの分子・細胞基盤と免疫応答制御

    Grant number：21H02653

    2021.4 - 2024.3

    System name：科学研究費助成事業

    Research category：基盤研究(B)

    Awarding organization：日本学術振興会

    片貝 智哉, 奥田 修二郎, 平島 正則

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

    リンパ節において、リンパ管を介して到達した抗原や液性因子に対する素早い応答は、リンパ洞の独特な組織構造と濾過機能に依存し、免疫・生理学的にも極めて重要な過程であると考えられる。しかし、このリンパ洞フィルターの構造や機能の詳細については未だ不明な点が多い。本研究は、リンパ節の特定領域に局在する特殊なリンパ管内皮細胞、間質ストローマ細胞、組織マクロファージにより構成されるリンパ洞フィルターの組織・細胞構造の分子基盤と構築原理、および免疫・生理学的意義の究明を目的とする。
    初年度は、野生型マウスや各種遺伝子発現レポーターマウスを用いて、リンパ節の洞内皮細胞、ストローマ細胞、マクロファージを含む免疫細胞の各種マーカーについて、共焦点および多光子励起レーザー顕微鏡による高解像度顕微観察を行い、リンパ洞フィルターの分子細胞構成・微細構造の詳細を明らかにした。また、蛍光標識デキストラン(分子量可変)、ポリスチレンビーズ(粒径可変)、黄色ブドウ球菌、酵母菌、LPS、卵白アルブミン(OVA)をマウス皮下に投与し、浸出リンパ節のリンパ洞フィルターによる捕捉・移送の経時的観察を行うとともに、フローサイトメトリーによりマクロファージサブセットへの取り込みを定量的に評価した。さらに、クロドロン酸内包リポソーム投与によるマクロファージ除去の影響を検討した。これらの解析により、髄洞の一部が網目状のリンパ管内皮細胞ネットワークと髄質マクロファージにより特殊な物理フィルター構造を形成し、リンパ節におけるリンパ液フィルターの本体であることを明確にした。我々は、この領域を辺縁髄洞接続帯（SMB）領域と名付けた。

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  • 血小板のリンパ組織発生における役割：生理活性物質の運び手としての血小板

    Grant number：20H03709

    2020.4 - 2023.3

    System name：科学研究費助成事業

    Research category：基盤研究(B)

    Awarding organization：日本学術振興会

    井上 克枝, 築地 長治, 平島 正則, 佐々木 知幸, 白井 俊光

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    Grant amount：\8840000 （ Direct Cost: \6800000 、 Indirect Cost：\2040000 ）

    私達は、肺とリンパ管の発生にはリンパ管内皮の膜蛋白ポドプラニン(PDPN)と血小板活性化受容体CLEC-2の結合により活性化された血小板から放出されるTGF-βが必須であることを報告した。CLEC-2 nullマウスでは全身のリンパ節が欠損し、肺、肝臓などにリンパ球の集簇した異所性リンパ組織（ELS）が認められた。以上より私達は「胎生期に生理活性物質を満載した血小板が、CLEC-2を介して様々な細胞のPDPNに触れ、特異的な箇所で活性物質を放出して器官発生が進行する」という全身に共通の血小板による発生制御機構が存在すると考えた。本課題ではリンパ節発生をモデルとし、血小板がいつ、どこで、どのようにしてリンパ節発生を制御するかと、血小板が運ぶ生理活性物質の実態を明らかにする。
    令和2年度までに、CLEC-2下流のシグナル分子であるSyk null マウス、PDPN null マウス、リンパ管特異的 PDPN 欠損マウスには鼠経リンパ節が欠如していることを見出し、リンパ節の形成には血小板活性化とリンパ管内皮 PDPN が必要であることが示された。しかし、令和3年度にリンパ管特異的 PDPN 欠損マウスのリンパ節をさらに調べたところ、小型のリンパ節が確認される個体も存在した。文献的には、Prox1欠損マウスなど、リンパ管が欠損したマウスでも、リンパ節は認められるが、通常よりも小型と報告されている。また、リンパ節を形成するLTi, LTo細胞でのPDPNを検討するため、免疫染色を行ったところ、CD3陽性のLTi細胞の周囲を取り囲むように、PDPN陽性のLTo様細胞が認められた。以上より、リンパ管内皮PDPNは、リンパ節原基の形成には不要だが、その成熟には必要であると考えた。リンパ節の成熟には、LTo細胞のPDPNが関与するとの仮説を立てた。

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  • ヒト胎児疾患モデルマウスの新規スクリーニング法の確立

    2017.4 - 2019.3

    System name：学術研究助成基金助成金／挑戦的研究（萌芽）

    平島 正則

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  • 生理的リンパ管・静脈吻合の形成機構と機能的意義

    2014.4 - 2017.3

    System name：学術研究助成基金助成金／基盤研究(C)

    平島 正則

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  • A-STEP「高眼圧の早期診断と創薬に向けたスクリーニング系の開発」

    2013

    System name：研究成果最適展開支援プログラム フィージビリティスタディステージ 探索タイプ

    平島 正則

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  • リンパ管腔形成と維持におけるＡｓｐｐ１の役割と分子機構

    2012.4 - 2014.3

    System name：科学研究費補助金／新学術領域研究

    平島 正則

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  • リンパ管内皮細胞の分子生物学的解析～プロスタノイドレセプターを巡って～

    2010

    System name：科学研究費補助金／基盤研究(C)

    野村 正

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    Grant type：Competitive

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  • 胎生期浮腫を示す内皮細胞遺伝子変異マウスの病態と分子機構

    2010

    System name：科学研究費補助金／基盤研究(C)

    平島 正則

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    Authorship：Principal investigator  Grant type：Competitive

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  • Analysis of the function of Rap1-activating factors which mediate the cross-talks between different species of small G proteins

    Grant number：20390080

    2008 - 2010

    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

    KATAOKA Tohru, SATOH Takaya, SHIMA FUMI, EDAMATSU Hironori, HIRASHIMA Masanori

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    Grant amount：\19630000 （ Direct Cost: \15100000 、 Indirect Cost：\4530000 ）

    RA-GEF-1, RA-GEF-2, and phospholipase Cε? (PLCε) are specific activators (guanine nucleotide exchange factors) for Rap1, which mediate cross-talks between different species of small G proteins. We have elucidated crucial functions of RA-GEF-1 in fetal blood vessel formation and neuronal migration, of RA-GEF-2 in sperm formation, and of PLCε in inflammation and carcinogenesis through generation and phenotypic characterization of whole body and conditional knockout mice of the respective genes.

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  • 血管内皮細胞の動・静脈アイデンティティーを決定する細胞外環境

    2007

    System name：科学研究費補助金／特定領域研究

    平島 正則

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    Authorship：Principal investigator  Grant type：Competitive

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  • マウス胚における動・静脈形成

    2007

    System name：科学研究費補助金／若手研究(B)

    平島 正則

    　 More details

    Authorship：Principal investigator  Grant type：Competitive

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Teaching Experience (researchmap)

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Teaching Experience

  • 人体の構造

    2024
    Institution name：新潟大学

  • 医学論文を読む(ジャーナルクラブ)A

    2023
    Institution name：新潟大学

  • 先端医科学研究概説

    2022
    -
    2023
    Institution name：新潟大学

  • 人体の構造と機能II(生理学)

    2021
    Institution name：新潟大学

  • 基礎薬理

    2019
    Institution name：新潟大学

  • 先端医科学研究概説

    2019
    -
    2023
    Institution name：新潟大学

  • 統合臨床医学

    2019
    -
    2020
    Institution name：新潟大学

  • 医学研究実習

    2019
    -
    2020
    Institution name：新潟大学

  • 病態薬理Ⅱ

    2019
    Institution name：新潟大学

  • 病態薬理Ⅰ

    2019
    Institution name：新潟大学

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