研究者詳細 - 寺井　崇二

【消化器疾患 state of arts II.肝・胆・膵】治療法をめぐる最近の進歩肝再生医療の現況と展望細胞療法を用いた肝再生医療自己骨髄細胞を用いた肝再生療法の開発

丸本芳雄, 寺井崇二, 坂井田功

医学のあゆみ別冊 ( 消化器疾患Ver.3 ) 495 - 498 2006年10月

rFGF2併用骨髄移植の肝線維化改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功

肝臓 47 ( Suppl.2 ) A477 - A477 2006年9月

消化器疾患の再生医療自己骨髄細胞を用いた肝臓再生療法の現状と今後の展開

寺井崇二, 石川剛, 坂井田功

日本消化器病学会雑誌 103 ( 臨増大会 ) A413 - A413 2006年9月

Proteomic analysis of serum marker proteins in recipient mice with liver cirrhosis after bone marrow cell transplantation 査読

Y Yokoyama, S Terai, T Ishikawa, K Aoyama, Y Urata, Y Marumoto, N Hiroshi, K Nakamura, K Okita, Sakaida, I

PROTEOMICS 6 ( 8 ) 2564 - 2570 2006年4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：WILEY-V C H VERLAG GMBH

We previously found that transplantation with bone marrow cells (BMCs) improves liver function and liver fibrosis in cirrhotic mice. In the presence of liver damage induced by carbon tetrachloride (CCI4), transplanted BMC migrated into the peri-portal region and trans-differentiated into hepatocytes that produce albumin. Thus under these conditions, BMC transplantation induces liver regeneration. Detecting serum marker proteins is important to monitor the recovery of liver function of cirrhotic mice after BMC transplantation. We therefore initially resolved proteins extracted from serum samples at 48 h after BMC transplantation by 2-DE and compared spot intensity between control and BMC groups of mice. Six protein spots increased in the BMC group compared with the control group. MS revealed that these spots comprised apolipoprotein A1 (apoA1), apolipoprotein C3 (apoC3), vitamin D-binding protein, alpha-l-antitrypsin and proteasome subunit alpha type 1. We subsequently confirmed the levels of apoA1 in serum and liver samples by immunoblotting. ApoA1 increased at early stage (48 h and 1 wk) after BMC transplantation in this mouse model of liver cirrhosis. The early elevation of apoA1 might be useful to predict liver regeneration in cirrhotic mice after BMC transplantation.

DOI： 10.1002/pmic.200500018

XBP-1は骨髄細胞から肝細胞への分化に関与する

丸本芳雄, 寺井崇二, 水永裕子, 松本俊彦, 浦田洋平, 青山浩司, 石川剛, 坂井田功

肝臓 47 ( Suppl.1 ) A292 - A292 2006年4月

メダカを用いた新規脂肪肝モデルの作成と,脂肪肝形成過程における遺伝子発現の検討

松本俊彦, 寺井崇二, 丸本芳雄, 仁科博史, 坂井田功

肝臓 47 ( Suppl.1 ) A97 - A97 2006年4月

肝線維化の分子機構と治療 rFGF2併用骨髄移植の肝線維化改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功

肝臓 47 ( Suppl.1 ) A41 - A41 2006年4月

Protein level of apolipoprotein E increased in human hepatocellular carcinoma 査読

Y Yokoyama, Y Kuramitsu, M Takashima, N Iizuka, S Terai, M Oka, K Nakamura, K Okita, Sakaida, I

INTERNATIONAL JOURNAL OF ONCOLOGY 28 ( 3 ) 625 - 631 2006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：PROFESSOR D A SPANDIDOS

Many reports suggest that hepatic steatosis leads to hepatocellular carcinoma (HCC), including hepatitis C virus or non-alcoholic steatollepatitis. Proteomic study Of tumor tissues from HCC patients, focusing oil apolipoprotein (apo) of apoA1, apoB 100 and apoE, was performed by immunoblotting. Although the significant changes of apoA1 or apoB 100 could not be shown statistically, the irninunoblotting showed the increase in protein level of apoE in the tumor tissues of 88% of patients without increase of apoE gene expression and serum level. These results suggest the accumulation of apoE by impaired secretion. Moreover, immunoblot analysis oil twodimensional electrophoresis showed a strong possibility that sialylated forms of apoE also were increased in tumorous tissues of HCC. ApoE level in tumorous tissues is frequently elevated and may be a good histological marker for HCC.

炎症と発癌肝持続炎症環境下における小胞体ストレス関連分子XBP-1とHSPの発現についての解析

丸本芳雄, 寺井崇二, 坂井田功

日本消化器病学会雑誌 103 ( 臨増総会 ) A127 - A127 2006年3月

Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes 査読

T Ishikawa, S Terai, Y Urata, Y Marumoto, K Aoyama, Sakaida, I, T Murata, H Nishina, K Shinoda, S Uchimura, Y Hamamoto, K Okita

CELL AND TISSUE RESEARCH 323 ( 2 ) 221 - 231 2006年2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：SPRINGER

We have developed an in vivo mouse model, the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model, and have previously reported that transplanted GFP-positive bone marrow cells (BMCs) differentiate into hepatocytes via hepatoblast intermediates. Here, we have investigated the growth factors that are closely related to the differentiation of transplanted BMCs into hepatocytes, and the way that a specific growth factor affects the differentiation process in the GFP/CCl4 model. We performed immunohistochemical analysis to identify an important growth factor in our model, viz., fibroblast growth factor (FGF). In liver samples, the expression of FGF1 and FGF2 and of FGF receptors (FGFRs; FGFR1, FGFR2) was significantly elevated with time after bone marrow transplantation (BMT) compared with other factors, and co-expression of GFP and FGFs or FGFRs could be detected. We then analyzed the effect and molecular mechanism of FGF signaling on the enhancement of BMC differentiation into hepatocytes by immunohistochemistry, immunoblotting, and microarray analysis. Treatment with recombinant FGF (rFGF), especially rFGF2, elevated the repopulation rate of GFP-positive cells in the liver and significantly increased the expression of both Liv2 (hepatoblast marker) and albumin (hepatocyte marker). Administration of rFGF2 at BMT also raised serum albumin levels and improved the survival rate. Transplantation of BMCs with rFGF2 specifically activated tumor necrosis factor-alpha (TNF-alpha) signaling. Thus, FGF2 facilitates the differentiation of transplanted BMCs into albumin-producing hepatocytes via Liv2-positive hepatoblast intermediates through the activation of TNF-alpha signaling. Administration of FGF2 in combination with BMT improves the liver function and prognosis of mice with CCl4-induced liver damage.

DOI： 10.1007/s00441-005-0077-0

【ここまで進んだ幹細胞研究と再生医療2006 幹細胞の分化を運命づけるメカニズムから臨床応用の取り組み,産業化の展望まで】幹細胞の臨床応用ここまで来ている再生医療自己骨髄細胞を用いた肝臓再生療法の開発基礎研究から臨床研究へ

石川剛, 寺井崇二, 坂井田功

実験医学 24 ( 2 ) 268 - 273 2006年1月

記述言語：日本語出版者・発行元：(株)羊土社

難治性肝疾患に対する新たな治療法の開発を目指して,われわれは骨髄幹細胞の可塑性に着目し基礎研究を進めてきた.慢性炎症という特殊環境下(分化Niche)において骨髄細胞が肝細胞へと分化し,さらにその過程で肝合成能・肝線維化・生命予後が有意に改善するという動物実験の結果を基盤として,われわれは2003年11月より国内初の臨床研究「自己骨髄細胞を用いた肝臓再生療法」を開始するに至った.今後より効率の良い治療法の開発に向けてさらなる基礎・臨床研究を重ね,詳細な解析・検討を進めていこうと考えている(著者抄録)

脂肪肝に対するイコサペント酸エチル(エパデールS)の有用性の検討

松本俊彦, 寺井崇二, 坂井田功

肝臓 46 ( Suppl.3 ) A562 - A562 2005年11月

急性肝不全における肝再生療法の現状 rFGF2併用骨髄移植による肝障害改善効果とその分子制御機構

石川剛, 寺井崇二, 坂井田功, 沖田極

肝臓 46 ( 11 ) 678 - 678 2005年11月

肝病変進展抑制をめざす新しい視点基礎と臨床 rFGF2併用骨髄移植による肝病変改善効果とその分子制御機構

石川剛, 寺井崇二, 沖田極

日本消化器病学会雑誌 102 ( 臨増大会 ) A574 - A574 2005年9月

肝病変進展抑制をめざす新しい視点基礎と臨床 rFGF2併用骨髄移植による肝病変改善効果とその分子制御機構

石川剛, 寺井崇二, 沖田極

肝臓 46 ( Suppl.2 ) A374 - A374 2005年9月

Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells 査読

JH Shen, Sakaida, I, K Uchida, S Terai, K Okita

LIFE SCIENCES 77 ( 13 ) 1502 - 1515 2005年8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

Leptin is now recognized as a proinflammatory cytokine and thought to be a progressive factor for nonalcoholic steatohepatitis (NASH). Here we showed the effects of leptin on the production of TNF-alpha(tumor necrosis factor-alpha) by Kupffer cells (KCs) with signal transduction. Leptin enhanced TNF-alpha production accompanied by a dose-dependent increase of MAPK activity in lipopolysaccharide (LPS)-stimulated KCs. SB203580 and JNK inhibitor I, specific inhibitors of P38 and JNK, inhibited TNF-alpha production in KCs but PD98059, an inhibitor of the ERK pathway, did not affect TNF-alpha production by KCs. Recombinant constitutively active adenovirus (Ad)-MKK6 and-MKK7 increased TNF-alpha production in KCs with activation of P38 and JNK without any change by Ad-MEK1 delivery. On the other hand, KCs isolated from the Zucker rat (fa/fa), a leptin receptor-deficient rat, showed reduced production of TNF-alpha on stimulation with LPS. The delivery of Ad-MKK6 and-MKK7, but not Ad-MEK1, increased TNF-alpha production in KCs of Zucker rats with activation of P38 and JNK. Addition of leptin to normal rats increased LPS-induced hepatic TNF-alpha production in vivo and leptin receptor-deficient Zucker rats showed reduced hepatic TNF-alpha production on addition of LPS in vivo. These findings indicate that P38 and JNK pathways are involved in the signal transduction of leptin enhancement of LPS-induced TNF-alpha production. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2005.04.004

Human homologue of maid is a useful marker protein in hepatocarcinogenesis 査読

T Takami, S Terai, Y Yokoyama, H Tanimoto, K Tajima, K Uchida, T Yamasaki, Sakaida, I, H Nishina, SS Thorgeirsson, K Okita

GASTROENTEROLOGY 128 ( 5 ) 1369 - 1380 2005年5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：W B SAUNDERS CO

Background & Aims: Human homologue of maid (HHM) is a helix-loop-helix (HLH) transcriptional regulatory protein that is involved in the hepatic stem cell development and differentiation. We analyzed the potential involvement of HHM in hepatocarcinogenesis. Methods: We analyzed HHM expression in the choline-deficient L-amino acid defined (CDAA) diet model of rat hepatocarcinogenesis and in human adenomatous hyperplasia (AH) and hepatocellular carcinoma (HCC) biopsy samples. We assessed the effects of HHM on cell proliferation. We screened proteins that bind to HHM protein using a yeast 2-hybrid screen. Results: High HHM expression was seen in foci and HCC induced in the rat CDAA diet model. HHM protein was expressed in 23 of 32 AH samples (72%), 19 of 28 well-differentiated HCC samples (68%), and 9 of 18 poorly-moderately differentiated HCC samples (50%). Over-expressed HHM enhanced the S phase. HHM interference RNA significantly inhibited cell proliferation. A yeast 2-hybrid screen identified Jun activation domain-binding protein I (Jab1) as a binding partner for HHM. We confirmed HHM and Jab1 binding by immunoprecipitation and immunofluorescent histochemistry. The expression of Jab1 was found in human AH and HCC samples. We found an association between levels of expression of HHM and those of Jabl in AH and HCC tissues examined (P =.027 by χ(2) test). Conclusions: High-level HHM expression was found from the very early stages of hepatocarcinogenesis, suggesting that HHM may be a useful marker protein to detect.

DOI： 10.1053/j.gastro.2005.03.014