Analysis on molecular mechanisms of liver reconstitution by transplanted hepatic cells

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590833
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: AZUMA Seishin (CHEN Cheng-Hsin) 東京医科歯科大学, 医学部・附属病院, 助教 (10376783)
• Co-Investigator(Kenkyū-buntansha): KAKINUMA Sei 東京医科歯科大学, 大学院・医歯学総合研究科, 寄附講座教員(講師) (30372444) ; SAKAMOTO Naoya 東京医科歯科大学, 大学院・医歯学総合研究科, 寄附講座教員(准教授) (10334418) ; WATANABE Mamoru 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (10175127)
• Co-Investigator(Renkei-kenkyūsha): SUZUKI Shinji 東京医科歯科大学, 大学院・医歯学総合研究科, 助教 (10456212)
• Project Period (FY): 2009 – 2011
• Keywords: 肝臓学

Research Abstract

Investigators of this research project have modulated the expression of target molecules of primary murine hepatic stem/progenitor cells purified by cell surface markers, and analyzed on the molecular mechanisms of liver repopulation by transplanted cells. We found that CD13 is a useful marker for enrichment of hepatic stem/progenitor cells. We also found that Sall4-mediated signaling pathway regulates the biliary differentiation of hepatic stem/progenitor cells. Our data indicated that modulation of MMP increases to the repopulation of recipient livers by donor cells. These studies contribute to the progress of autologous stem cell therapy against liver diseases.

Research Products

• [Journal Article] Data Mining Analysis of Hepatocellular Carcinoma Risk Predictors in Chronic Hepatitis C (2012)
  • Author(s): Kurosaki M, Hiramatsu N, Sakamoto M, Suzuki Y, iwasaki M, Tamori A, Matsuura K, Kakinuma S, Sugauchi F, Sakamoto N, Nakagawa M, Izumi NHiramatsu N, Sakamoto M, Suzuki Y, iwasaki M, Tamori A, Matsuura K, Kakinuma S, Sugauchi F, Sakamoto N
  • Journal Title: C.J Hepatol Volume: 56(3) Pages: 602-8
• [Journal Article] Identification of novel N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication (2012)
  • Author(s): Kusano-Kitazume A, Sakamoto N, Okuno Y, Sekine-Osajima Y, Nakagawa M, Kakinuma S, Kiyonashi K, Nitta S, Murakawa M, Azuma S, Nishimura-Sakurai Y, Hagiwara M, Watanabe M
  • Journal Title: Antimicrob Agent Chemother Volume: 56(3) Pages: 1315-23
• [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis (2012)
  • Author(s): Kurosaki M, Hiramatsu N, Sakamoto M, Suzuki Y, Iwasaki M, Tamori A, Matsuura K, Kakinuma S, Sakaguchi F, Sakamoto N, Nakagawa M, Izumi N
  • Journal Title: C.J Hepatol Volume: 56(3) Pages: 602-8
• [Journal Article] Ochanomizu Liver Conference Study Group : Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C (2012)
  • Author(s): Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K, Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M, Watanabe M
  • Journal Title: Hepatol Int Volume: (in press)
• [Journal Article] Association of gene expression involving innate immunity and genetic variation in IL28B with antiviral response (2011)
  • Author(s): Asahina Y, Tsuchiya K, Muraoka M, TanakaK, Suzuki Y, Tamaki N, Hoshioka Y, Yasui Y, Katoh T, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nitta S, Sakamoto N, Izumi N
  • Journal Title: Hepatology Volume: 55(1) Pages: 20-29
• [Journal Article] Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice (2011)
  • Author(s): Kakinuma S, Onozuka I, Kamiya A, Miyoshi M, Sakamoto N, Kiyohashi K, Watanabe T, Funaoka Y, Ueyama M, NakagawaM, Koshikawa N, Seiki M, Nakauchi H, and Watanabe M
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 134-140
• [Journal Article] Pre-treatment prediction of response topegylated-interferon plus ribavirin forchronic hepatitis C using genetic polymorphism in IL28B and viral factors (2011)
  • Author(s): Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, SugiyamaM, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M
  • Journal Title: JHepatol Volume: 54 Pages: 439-448
• [Journal Article] Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91 (2011)
  • Author(s): Funaoka Y, Sakamoto N, Suda G, Itsui Y, Nakagawa M, Kakinuma S, Watanabe T, Nitta S, Kitazume A, Kiyohashi K, Murakawa M, Azuma S, Tsuchiya K, Watanabe M
  • Journal Title: J Virol Volume: 85 Pages: 5986-94
• [Journal Article] Analysis of the complete open reading frame of genotype 2b hepatitis C virus in association with the response to peginterferon and ribavirin therapy (2011)
  • Author(s): Kadokura M, Maekawa S, Sueki R, Miura M, Komase K, Shindo H, Amemiya F, Uetake T, Inoue T, Sakamoto M, Nakagawa M, Sakamoto N, Watanabe M, Enomoto N
  • Journal Title: PLoS One Volume: 6(9) Pages: e24514
• [Journal Article] Pretreatment prediction of anemia progression by pegylated interferon a2b plus ribavirin combination therapy in chronic hepatitis C infection : Decision-tree analysis (2011)
  • Author(s): Hiramatsu N, Kurosaki M, Sakamoto N, Iwasaki M, Sakamoto M, Suzuki Y, Sakaguchi F, Tamori A, Kakinuma S, Matsuura K, Izumi N
  • Journal Title: JGastroenterol Volume: 46 Pages: 1111-19
• [Journal Article] Inhibitory effect of triterpenoid compound, with or without interferon-alpha, on hepatitis C virus infection (2011)
  • Author(s): Watanabe T, Sakamoto N, Nakagawa M, Kakinuma S, Itsui Y, Nishimura-Sakurai Y, Ueyama M, Funaoka Y, Kitazume A, Nitta S, Kiyohashi K, Murakawa M, Azuma S, Tsuchiya K, Oooka S, Watanabe M
  • Journal Title: Antimicrob Agent Chemother Volume: 55 Pages: 2537-45
• [Journal Article] Serum interleukin-6 levels can predict resistance to treatment of chronic hepatitis C infection with pegylated-interferon alpha 2b plus ribavirin (2011)
  • Author(s): Ueyama M, Nakagawa M, Sakamoto N, Onozuka I, Funaoka Y, Watanabe T, Nitta S, Kiyohashi K, Kitazume A, Murakawa M, Nishimura-Sakurai Y, Sekine-Osajima Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: Antivir Ther Volume: 16 Pages: 1081-1091
• [Journal Article] Association of IL28B polymorphism withresponse to pegylated-interferon alpha plusribavirin combination therapy in patientswith chronic genotype 2 hepatitis C (2011)
  • Author(s): Sakamoto N, Nakagawa M, Tanaka Y, Sekine-Osajima Y, Ueyama M, Kurosaki M, Nishida N, Tamori A, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Hige S, Ito Y, Tanaka E, Hiasa Y, Izumi N, Tokunaga K, Mizokami M, Watanabe M
  • Journal Title: JMedical Virol Volume: 83 Pages: 871-878
• [Journal Article] Lnk/Sh2b3 regulatesintegrin aIIbb3 outside-in signaling inplatelets leading to stabilization ofdeveloping thrombus in vivo (2010)
  • Author(s): Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, Kakinuma S, Yamazaki S, Okamura S, Tamura N, Goto S, Sawaguchi A, Manabe I, Takatsu K, NakauchiH, Takaki S, Eto K
  • Journal Title: J Clin Invest Volume: 120 Pages: 179-190
• [Journal Article] Cell culture and in-vivo analyses of plaque-derived cytopathic hepatitis C virus mutants (2010)
  • Author(s): Mishima K, Sakamoto N, Sekine-Osajima Y, Nakagawa M, Itsui Y, Azuma S, Kakinuma S, Tuchiya K, Imamura M, Chayama K, Wakita T, Watanabe M
  • Journal Title: Virology Volume: 405 Pages: 361-369
• [Journal Article] IL-6-mediated intersubgenotypic variation of interferon sensitivity in hepatitis C virus genotype 2a/2b chimeric clones (2010)
  • Author(s): Suda G, Sakamoto N, Itsui Y, Nakagawa M, Mishima K, Onuki-Karakama Y, Yamamoto M, Funaoka Y, Watanabe T, Kiyohashi K, Nitta S, Azuma S, Kakinuma S, Tuchiya K, Imamura M, Hiraga N, Chayama K, Watanabe M
  • Journal Title: Virology Volume: 407 Pages: 80-90
• [Journal Article] Inhibition of HCV replication by a specific inhibitor of serin-arginine-rich protein kinase (2010)
  • Author(s): Karakama Y, Sakamoto N, Itsui Y, Nakagawa M, Tasaka-Fujita M, Nishimura-Sakurai Y, Kakinuma S, Oooka S, Azuma S, Tsuchiya K, Onogi H, Hagiwara M, Watanabe M
  • Journal Title: Antimicrob AgentChemother Volume: 54 Pages: 3179-86
• [Journal Article] ITPA gene variant protects against anemia induced by pegylated interferon-alfa and ribavirin therapy for Japanese patients with chronic hepatitis C (2010)
  • Author(s): Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Honda M, Ito K, Mizokami M, Watanabe M
  • Journal Title: Hepatol Res Volume: 40 Pages: 1063-1071
• [Journal Article] Comparison of HCV-associated gene expression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells (2010)
  • Author(s): Nishimura-Sakurai Y, Sakamoto N, Mogushi K, Nagaie S, Nakagawa M, Itsui Y, Sekine-Osajima Y, Tasaka-Fujita M, Onuki-Karakama Y, Suda G, Mishima M, Yamamoto M, Ueyama M, Funaoka Y, Watanabe T, Chen CH, Kakinuma S, Tsuchiya K, Tanaka H, Enomoto N, Watanabe
  • Journal Title: J Gastroentorol Volume: 45 Pages: 523-36
• [Journal Article] Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection (2010)
  • Author(s): Nakagawa M, Sakamoto N, Ueyama M, Mogushi K, Nagaie S, Itsui Y, Azuma S, Kakinuma S, Tanaka H, Enomoto N, Watanabe M
  • Journal Title: J Gastroentorol Volume: 45 Pages: 656-665
• [Journal Article] Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice (2009)
  • Author(s): Kamiya A, Kakinuma S, Yamazaki Y, Nakauchi H
  • Journal Title: Gastroenterology Volume: 137 Pages: 1114-26
• [Journal Article] Sall4 regulates cell fate decision of fetal hepatic stem/progenitor cells (2009)
  • Author(s): Oikawa T, Kamiya A, Kakinuma S, Zeniya M, Nishinakamura R, Tajiri H, Nakauchi H
  • Journal Title: Gastroenterology Volume: 136 Pages: 1000-11
• [Journal Article] Antiviral effects of the interferon-induced protein GBP-1 and its interaction with the hepatitis C virus NS5B protein (2009)
  • Author(s): Itsui Y, Sakamoto N, Kakinuma S, Nakagawa M, Sekine-Osajima Y, Tasaka-Fujita M, Nishimura-Sakurai Y, Suda G, Karakama Y, Mishima K, Yamamoto M, Watanabe T, Ueyama M, Funaoka Y, Azuma S, Watanabe M
  • Journal Title: Hepatology Volume: 50 Pages: 1727-37
• [Journal Article] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C (2009)
  • Author(s): Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M
  • Journal Title: NatGenet Volume: 41 Pages: 1105-1109
• [Journal Article] Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture
  • Author(s): Yamamoto M, Sakamoto N, Nakamura T, Itsui Y, Nakagawa M, Nishimura-Sakurai Y, Kakinuma S, Azuma S, Kato T, Wakita T, Watanabe M
  • Journal Title: Hepatol Res
• [Presentation] Treatment and outcomes for elderly patientswith hepatocellular caricinoma (2012)
  • Author(s): Azuma S, Sakamoto N, Sakurai Y, Nakagawa M, Kakinuma S, Watanabe M
  • Organizer: 22nd Conference of the Asian Pacific Association for the Study of the Liver, Feb-18-2012, Taipei, Taiwan
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2012-02-18
• [Presentation] Loww of Wnt5A promotes biliary differentiation of murine hepatic stem/progenitor cells (2011)
  • Author(s): Kiyohashi K, Kakinuma S, Kamiya A, Sakamoto N, Nakauchi H, Watanabe M
  • Organizer: 62 nd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA. USA
  • Year and Date: 2011-11-06
• [Presentation] ITPA gene variant protects against treatment-induced anemia and improves viral clearance by pegylated interferon-alfa and ribavirin therapy in chronic hepatitis C patients (2011)
  • Author(s): Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Mizokami M, Watanabe M
  • Organizer: 62 nd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA. USA
  • Year and Date: 2011-11-05
• [Presentation] MMP-2 and MMP-14 derived from donor cells enhance therapeutic efficacy of liver cell transplantation in mice (2011)
  • Author(s): Kakinuma S, Kamiya A, Sakamoto N, Nakauchi H, Watanabe M
  • Organizer: 62nd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2011-11-04
• [Presentation] 高齢者肝細胞癌患者に対する治療方法とその成績 (2011)
  • Author(s): 東正新、坂本直哉、桜井幸、吉野耕平、幾世橋佳、新田沙由梨、北詰晶子、村川美也子、中川美奈、柿沼晴、渡辺守
  • Organizer: JDDW 2011(第15回日本肝臓学会大会)
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] 肝線維化プロセスにおけるMatrixMetalloproteinase-2の機能 (2011)
  • Author(s): 柿沼晴、紙谷聡英、小野塚泉、東正新、坂本直哉、中内啓光、渡辺守
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] Analysis of cell surface molecules on transplantable hepatic progenitor cells in mouse fetal neonatal livers (2010)
  • Author(s): Kakinuma S, Kamiya A, Sakamoto N, Watanabe M, Nakauchi H
  • Organizer: 1st JSGE International Topic Conference
  • Place of Presentation: Kamakura, JAPAN
  • Year and Date: 20100900
• [Presentation] 細胞移植時のドナーキメリズム形成に対するMatrix Metalloproteinaseの関与 (2010)
  • Author(s): 柿沼晴、中内啓光、渡辺守
  • Organizer: JDDW2010(第14回日本肝臓学会大会・第52回日本消化器病学会大会)
  • Place of Presentation: 横浜
  • Year and Date: 2010-10-13
• [Presentation] 肝臓細胞移植におけるドナー由来MatrixMetalloproteinaseの関与 (2010)
  • Author(s): 柿沼晴、紙谷聡英、坂本直哉、渡辺守、中内啓光
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: 山形
  • Year and Date: 2010-05-28
• [Book] iPS細胞とDirect ConversionG. I. Research (2011)
  • Author(s): 柿沼晴
  • Total Pages: 78-79
  • Publisher: 先端医学社
• [Book] 肝細胞及び肝幹・前駆細胞移植におけるMatrix Metalloproteinaseの関与分子標的薬その作用機序と効果予測 (2010)
  • Author(s): 柿沼晴
  • Total Pages: 159-166
  • Publisher: アークメディア