研究者詳細 - 寺井　崇二

Helix-loop-helix(HLH)型転写制御分子Human homologue of Maid(HHM)からみた肝発癌

高見太郎, 寺井崇二, 谷本治子, 坂井田功, 沖田極

山口医学 53 ( 3 ) 185 - 185 2004年6月

肝発癌におけるHuman homologue of Maid(HHM)の機能とその発現制御

高見太郎, 寺井崇二, 沖田極

肝臓 45 ( Suppl.1 ) A96 - A96 2004年4月

肝硬変患者の就寝前肝不全経口栄養剤投与についての検討

土屋昌子, 坂井田功, 青山浩司, 石川剛, 田島邦彦, 横山雄一郎, 大森薫, 川口浩太郎, 高見太郎, 木村輝昭, 寺井崇二, 山崎隆弘, 黒川典枝, 沖田極

肝臓 45 ( Suppl.1 ) A258 - A258 2004年4月

骨髄細胞による肝再生モデルマウスにおける血清プロテオミクス

横山雄一郎, 寺井崇二, 大森薫, 青山浩司, 石川剛, 高見太郎, 坂井田功, 沖田極

肝臓 45 ( Suppl.1 ) A225 - A225 2004年4月

骨髄細胞移植による肝線維化治療の検討

坂井田功, 山浩司, 石川剛, 大森薫, 寺井崇二, 仁科博史, 沖田極

マトリックス研究会大会 ( 51 ) 52 - 52 2004年4月

【幹細胞と消化器疾患】骨髄細胞から肝細胞への分化転換の制御機構の解析とその臨床応用自己骨髄細胞を用いた肝臓再生療法の基礎的検討

寺井崇二, 石川剛, 大森薫, 青山浩司, 坂井田功, 沖田極

G.I.Research 12 ( 2 ) 117 - 125 2004年4月

記述言語：日本語出版者・発行元：(株)先端医学社

われわれは「自己骨髄細胞を用いた肝臓再生療法」の開発のため,骨髄細胞の肝細胞への分化評価モデル"GFP/CCl4モデル"を開発した.このモデルにおいては持続肝障害が続く肝硬変症において骨髄細胞は肝臓へ定着し肝細胞への分化転換していく.一方,肝発生過程において炎症性シグナルは肝芽細胞の発生,増殖は必須であり,肝発生と再生には共通のメカニズムが存在する.さらに,骨髄中の肝幹細胞群の同定のための新規モノクローナル抗体Liv 8抗体を用いて基礎的検討をおこなった.これらの結果は自己骨髄細胞を用いた肝臓再生療法は次世代の治療法になり得る可能性を示したのでここに紹介する(著者抄録)

線維芽細胞増殖因子は骨髄細胞から肝細胞への分化転換を促進する

石川剛, 寺井崇二, 浦田洋平, 丸本芳雄, 青山浩司, 大森薫, 坂井田功, 沖田極

肝臓 45 ( Suppl.1 ) A43 - A43 2004年4月

骨髄細胞から肝細胞への分化転換の素過程に関与する遺伝子群の抽出及び可視化

大森薫, 寺井崇二, 浦田洋平, 丸本芳雄, 石川剛, 青山浩司, 坂井田功, 仁科博史, 内村俊二, 浜本義彦, 沖田極

肝臓 45 ( Suppl.1 ) A84 - A84 2004年4月

Liv-8陰性分画骨髄細胞の移植による肝線維化改善の検討

青山浩司, 坂井田功, 浦田洋平, 丸本芳雄, 石川剛, 大森薫, 寺井崇二, 沖田極

肝臓 45 ( Suppl.1 ) A89 - A89 2004年4月

Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell 査読

Sakaida, I, K Hironaka, T Kimura, S Terai, T Yamasaki, K Okita

LIFE SCIENCES 74 ( 18 ) 2251 - 2263 2004年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

We have reported that Sho-saiko-to (TJ-9) prevents liver fibrosis in vivo. To gain further insights into the effect of TJ-9, the matrix metalloprotemases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) balance was examined. Hepatic stellate cells (HSCs) were isolated from male Wistar rats and cultured with TJ-9 (0-1000 mug/ml) on uncoated plastic dishes for 4 days. To elucidate the effects on the MMPs/TIMPs balance by TJ-9, quantitative analysis of type IV collagen-degrading activity, gelatin zymography and reverse zymography were carried out. Northern blot analysis was performed to determine the expression of MMP-2, 13 and TIMP-1 mRNAs. TJ-9 treatment resulted in dose-dependent upregulation of MMP-2, 13 mRNA and downregulation of TIMP-1 mRNA up to 500 mug/ml. Gelatin zymography, reverse zymography and quantitative analysis of type IV collagen-degrading activity confirmed that TJ-9 increased MMP-2 activity and prevented TIMP-1, 2 activities in a dose-dependent manner. SB203580 diminished the reduction of mRNA as well as the activity of TIMP-I by TJ-9 and induction of mRNA as well as the activity of MMP-2. These results show that TJ-9 increased MMP-2, 13 activity with reduced TIMP-1, 2 activities on HSCs possibly via P38 pathway. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2003.09.059

A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver 査読

N Yamamoto, S Terai, S Ohata, T Watanabe, K Omori, K Shinoda, K Miyamoto, T Katada, Sakaida, I, H Nishina, K Okita

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 313 ( 4 ) 1110 - 1118 2004年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

We previously reported a new in vivo model named as "GFP/CCl4 model" for monitoring the transdifferentiation of green fluorescent protein (GFP) positive bone marrow cell (BMC) into albumin-positive hepatocyte under the specific "niche" made by CCl4 induced persistent liver damage, but the subpopulation which BMCs transdifferentiate into hepatocytes remains unknown. Here we developed a new monoclonal antibody, anti-Liv8, using mouse E 11.5 fetal liver as an antigen. Anti-Liv8 recognized both hematopoietic progenitor cells in fetal liver at E 11.5 and CD45-positive hematopoietic cells in adult bone marrow. We separated Liv8-positive and Liv8-negative cells and then transplanted these cells into a continuous liver damaged model. At 4 weeks after BMC transplantation, more efficient repopulation and transdifferentiation of BMC into hepatocytes were seen with Liv8-negative cells. These findings suggest that the subpopulation of Liv8-negative cells includes useful cells to perform cell therapy on repair damaged liver. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2003.12.044

肝臓肝細胞癌の病態と診断

高見太郎, 寺井崇二, 沖田極

Annual Review消化器 2004 303 - 307 2004年1月

Strategy for the development of cell therapy using bone marrow cells to repair damaged liver 査読

S Terai, Sakaida, I, N Yamamoto, K Omori, K Okita

STEM CELL AND LIVER REGENERATION 51 - 56 2004年

記述言語：英語掲載種別：研究論文（国際会議プロシーディングス）出版者・発行元：SPRINGER-VERLAG TOKYO

Recently, the plasticity of stem cells in bone marrow to differentiate into other cell lineages has been reported. if we can use stem cells in bone marrow, we can easily isolate hepatic stem cells to regenerate liver. In particular, cell therapy using autologous bone marrow cells to regenerate blood vessels has already been done clinically. To develop cell therapy using bone marrow cells to repair damaged liver, we have to understand the mechanism by which bone marrow cells differentiate into hepatocytes. in this chapter, we report a strategy for the development of cell therapy for liver regeneration.

An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes 査読

S Terai, Sakaida, I, N Yamamoto, K Omori, T Watanabe, S Ohata, T Katada, K Miyamoto, K Shinoda, H Nishina, K Okita

JOURNAL OF BIOCHEMISTRY 134 ( 4 ) 551 - 558 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE BIOCHEMICAL SOC

The plasticity of bone marrow cells (BMCs) remains controversial. The present study found that persistent injury induces efficient trans-differentiation of BMCs into functional hepatocytes. Mice with liver cirrhosis induced by carbon tetrachloride were injected with 1 x 10(5) non-treated green fluorescent protein (GFP)-positive BMCs via the tail vein. In these mice, transplanted GFP-positive BMCs efficiently migrated into the peri-portal area of liver lobules after one day, repopulating 25% of the recipient liver by 4 weeks. In contrast, no GFP-positive BMCs were detected following transplantation into control mice with undamaged livers. BMCs trans-differentiated into functional mature hepatocytes via immature hepatoblasts. Serum albumin levels were significantly elevated to compensate for chronic liver failure in BMC transplantation. These results reveal that recipient conditions and microenvironments represent key factors for successful cell therapy using BMCs.

DOI： 10.1093/jb/mvg173

Arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and isovorin for patients with advanced hepatocellular carcinoma, pilot study: Is a high dose of the biochemical modulator effective? 査読

T Yamasaki, F Kurokawa, T Takami, K Omori, K Kawaguchi, M Tsuchiya, N Yamamoto, M Okamoto, K Hironaka, T Kimura, S Terai, Sakaida, I, K Okita

HEPATOLOGY RESEARCH 27 ( 1 ) 36 - 44 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI IRELAND LTD

The authors report the efficacy of arterial infusion chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), and leucovorin (LV) for patients with advanced hepatocellular carcinoma (HCC). In this study, we evaluated the efficacy of our regimen with high-dose LV, using isovorin (IV) (high dose group), comparing the previous regimen (low-dose LV; low dose group). This is a retrospective, historical, and non-controlled trial. In the high dose group (n = 15), one course of chemotherapy consisted of the daily administration of CDDP (10 mg/1 h, for 5 days) and IV (12.5 mg/10 min, for 5 days) followed by 5-FU (250 mg/5 h, for 5 days). In the low dose group (n = 9), changing to the administration of LV (12 mg/day), the same regimen was employed. In principle, we did this 20 times. In the high dose group, complete response (CR) was found in two patients, and partial response (PR) in six patients. Thus, the response rate was 53%. In the low dose group, CR was found in two patients, and PR in three patients. Thus, the response rate was 56%. There were no significant differences in the response rate (P = 0.71), the survival rate (P = 0.29) and the toxicity between the two groups. We considered the recommended dose of LV to be 12 mg/day in our regimen, although this is a preliminary study. (C) 2003 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1386-6346(03)00195-5

Leptin receptor-deficient Zucker (fa/fa) rat retards the development of pig serum-induced liver fibrosis with Kupffer cell dysfunction 査読

Sakaida, I, S Jinhua, K Uchida, S Terai, K Okita

LIFE SCIENCES 73 ( 19 ) 2491 - 2501 2003年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The aim of this study was to investigate the role of leptin in the development of liver fibrosis with Kupffer cell function using leptin receptor deficient rats. Male Zucker (fa/fa) and control (fa/-) rats received pig serum for 8 weeks. Animals were sacrificed to estimate the degree of liver fibrosis and stellate cell activation with the expression of alpha smooth muscle actin (alphaSMA). Microarray analysis was performed. Isolated Kuppfer cells of Zucker and control rats were treated with LPS. LPS uptake and TNF-alpha production were examined. Stellate cells were also isolated from Zucker and control rats. The expression of procollagen type I mRNAs was examined. Control rats developed liver fibrosis 8 weeks after injection of pig serum and showed an increased liver hydroxyproline content of 348 +/- 34 mug/g (n = 10) compared with Zucker rats (225 +/- 13, n = 10, P < 0.01). The procollagen type I mRNA level and alphaSMA expression of Zucker rats were also significantly reduced. Microarray analysis indicated significantly reduced expression of TNF-alpha, LPS-binding protein, urokinase-type plasminogen activator (uPA), IGF, IGF-binding protein (IGFBP)-3,5, and increased expression of apolipoprotein IV Isolated Kupffer cells of Zucker rats showed significantly reduced LPS uptake as well as TNF-alpha production compared with control rats. However, no significant change was observed in procollagen type I mRNA levels of isolated stellate cells after 4 days of culture on plastic dishes. These results suggest that leptin receptor deficiency retards the development of liver fibrosis due to the dysfunction of Kuppfer cells. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0024-3205(03)00653-2