Analysis on molecular mechanisms of proliferation and differentiation of hepatic stem/progenitor cells and development of animal model for treatment of liver diseases using hepatic stem cells

• Project/Area Number: 22790632
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 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 (30372444)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝臓学 / 再生医学 / 移植 / 細胞・組織 / 発生・分化 / 肝疾患治療 / 肝細胞移植

Research Abstract

Investigators of this research project have analyzed on the molecular mechanisms of differentiation and proliferation of primary hepatic stem/progenitor cells purified by cell surface markers. We have also studied whether modulation of several molecules improves therapeutic efficacy of transplantation using hepatic stem/progenitor cells. We found that Wnt5a and Wnt5a-related molecules control the biliary differentiation of hepatic stem/progenitor cells. Next, our data indicated that loss of MMP2 or MMP14 worsens the efficacy of transplantation using hepatic stem/progenitor cells. These studies contribute to the progress of regenerative medical science and autologous stem cell therapy against liver diseases.

Research Products

• [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, KakinumaS, Kiyonashi K, Nitta S, Murakawa M, AzumaS, 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 In
• [Journal Article] Age and total ribavirin dose is an independent predictor of relapse among early virological responders to peg-interferon plus ribavirin therapy in chronic hepatitis C revealed by data mining analysis (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, Yatsuhashi H, Izumi N.
  • Journal Title: Antivir Ther Volume: 17 Pages: 35-43
• [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C (2012)
  • Author(s): Kurosaki M, Sakamoto N, Nakagawa M, et al.
  • Journal Title: J Hepatol Volume: 56(3) Issue: 3 Pages: 602-608
  • DOI: 10.1016/j.jhep.2011.09.011
  • Peer Reviewed
• [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, MiyoshiM, Sakamoto N, Kiyohashi K, Watanabe T, Funaoka Y, Ueyama M, Nakagawa M, Koshikawa N, Seiki M, Nakauchi H, and Watanabe M.
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 134-140
• [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] 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, IzumiN.
  • Journal Title: J Gastroenterol 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] Conference Study Group. 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 and the Ochanomizu-Liver
  • Journal Title: Antivir Ther Volume: 16 Pages: 1081-1091
• [Journal Article] Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture (2011)
  • 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 Volume: 41 Pages: 258-269
• [Journal Article] Association of IL28B polymorphism with response to pegylated-interferon alpha plus ribavirin combination therapy in patients with 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] Pretreatment Prediction of Anemia Progression by Peginterferon Plus Ribavirin Therapy in Chronic Hepatitis C : Decision-Tree Analysis (2011)
  • Author(s): Hiramatsu N, Sakamoto N, et al.
  • Journal Title: J Gastroenterol Volume: 46(9) Issue: 9 Pages: 1111-1119
  • DOI: 10.1007/s00535-011-0412-z
  • Peer Reviewed
• [Journal Article] Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice. (2011)
  • Author(s): Kakinuma S, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Lnk/Sh2b3 regulates integrin aIIbb3 outside-in signaling in platelets leading to stabilization of developing thrombus in vivo (2010)
  • Author(s): Takizawa H, Nishimura S, Takayama N, OdaA, 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 Inve 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, ImamuraM, 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 Agent Chemother Volume: 54 Pages: 3179-86
• [Journal Article] ITPA gene variant protects against anemia induced by pegylated interferon-alfa and ribavirintherapy 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 geneexpression and cell signaling pathways in cells with or without HCV replicon and in replicon-cured cells (2010)
  • Author(s): Nishimura-Sakurai Y, Sakamoto N, MogushiK, 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, TsuchiyaK, Tanaka H, Enomoto N, Watanabe M.
  • Journal Title: J Gastroentorol Volume: 45 Pages: 523-36
  • NAID: 10027216127
• [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
  • NAID: 10027216778
• [Journal Article] IL-6-mediated intersubgenotypic variation of interferon sensitivity in hepatitis C virus genotype 2a/2b chimeric clones. (2010)
  • Author(s): Suda G, Kakinuma S, et al.
  • Journal Title: Virology Volume: 407 Pages: 80-90
  • Peer Reviewed
• [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, Kakinuma S, et al.
  • Journal Title: Hepatology Research Volume: 40 Pages: 1063-1071
  • Peer Reviewed
• [Presentation] MMP-2 and MMP-14 derived from donor cells enhance therapeutic efficacy of liver cell transplantation in mice (2011)
  • Author(s): Kakinuma S, et al.
  • Organizer: 62^<nd> Annual meeting of the American Association of the Study of Liver Disease
  • 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: 62th Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2011-11-04
• [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: 62th Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA. USA
  • Year and Date: 2011-11-04
• [Presentation] Noncanonical Wnt経路による肝幹/前駆細胞の分化制御 (2011)
  • Author(s): 幾世橋佳、柿沼晴、渡辺守
  • Organizer: JDDW 2011(第15回日本肝臓学会大会・第53回日本消化器病学会大会)
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-21
• [Presentation] 肝線維化プロセスにおけるMatrix Metalloproteinase-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: 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] Noncanonical Wnt経路によるマウス肝幹・前駆細胞の分化制御機構への関与 (2011)
  • Author(s): 幾世橋佳、柿沼晴、紙谷聡英、小野塚泉、中川美奈、坂本直哉、中内啓光、渡辺守
  • Organizer: 第47回日本肝臓学会総会(一般演題)
  • Place of Presentation: 東京
  • Year and Date: 2011-06-03
• [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: JDDW 2010(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] Analysis of Cell Surface Molecules on Transplantable Hepatic Progenitor Cells in Mouse Fetal and Neonatal Livers. (2010)
  • Author(s): Kakinuma S, et al.
  • Organizer: The 1^<st> International Topic Conference by Japanese Society of Gastroenterology
  • Place of Presentation: Kamakura, JAPAN
  • Year and Date: 2010-09-25
• [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(一般演題)
  • Place of Presentation: 山形
  • Year and Date: 2010-05-28
• [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: 1^<st> JSGE International Topic Conference
  • Place of Presentation: Kamakura, JAPAN
• [Presentation] Therapeutic model of hepatic cell transplantation without genetic liver injury in recipients (2010)
  • Author(s): Kakinuma S, Kamiya A, Sakamoto N, Watanabe M, Nakauchi H.
  • Organizer: FASEB Summer Research Conferences 2010, Liver growth, injury, and metabolism
  • Place of Presentation: Snowmass, CO, USA
• [Book] iPS細胞とDirect Conversion G. I. Research (2011)
  • Author(s): 柿沼晴
  • Publisher: 先端医学社
• [Book] iPS細胞とDirect Conversion (G.I.Research) (2011)
  • Author(s): 柿沼晴、渡辺守
  • Total Pages: 619
  • 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(アークメディア) (2010)
  • Author(s): 柿沼晴
• [Book] 分子標的薬 その作用機序と効果予測:肝細胞及び肝幹・前駆細胞移植におけるMatrix Metalloproteinaseの関与 (2010)
  • Author(s): 柿沼晴, 他分著(小俣政男編集)
  • Total Pages: 7
  • Publisher: アークメディア