Studies on molecular mechanisms regulating fate decision of hepatic stem cells and efficacy of hepatic stem cell transplantation

• Project/Area Number: 24590957
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KAKINUMA Sei 東京医科歯科大学, 医歯(薬)学総合研究科, 講師 (30372444)
• Co-Investigator(Kenkyū-buntansha): ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692) ; 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): KAMIYA Akihide 東海大学, 創造科学技術研究機構, 准教授 (30321904)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 発生・分化 / 移植 / 再生医学 / 肝疾患治療 / 細胞・組織

Outline of Final Research Achievements

Investigators of this research project have studied on the molecular mechanisms regulating differentiation and proliferation of primary hepatic stem/progenitor cells purified by cell surface markers and therapeutic efficacy of transplantation using hepatic stem/progenitor cells. We found that Wnt5a and Wnt5a-related signaling control the biliary differentiation of hepatic stem/progenitor cells. Next, our data indicated that MMP14 and MMP14-related signaling regulate luminal formation of bile ducts in developing liver, and that expression of MMP14 improves the efficacy of transplantation using hepatic stem/progenitor cells. These studies contribute to the progress of regenerative medical science and development of autologous stem cell therapy against chronic liver diseases.

Research Products

• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Journal Article] Primary hepatic neuroendocrine carcinoma with a cholangiocellular carcinoma component in one nodule. (2014)
  • Author(s): Kano Y, Kakinuma S, Goto F, Azuma S, Nishimura-Sakurai Y, Itsui Y, Nakagawa M, Kudo A, Tanabe M, Kirimura S, Amano T, Ito T, Akashi T, Asahina Y, Watanabe M.
  • Journal Title: Clin J Gastroenterol Volume: 7 Issue: 5 Pages: 449-454
  • DOI: 10.1007/s12328-014-0521-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Matrix Metalloproteinase-14 regulates the maturation of fetal hepatic stem/progenitor cells in mice (2014)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Azuma S, Asahina Y, Watanabe M
  • Journal Title: Heoatology Volume: 60
  • Peer Reviewed
• [Journal Article] Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C (2014)
  • Author(s): Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M, Izumi N.
  • Journal Title: J Gastroenterol Volume: in press Issue: 7 Pages: 1152-1162
  • DOI: 10.1007/s00535-013-0858-2
  • Peer Reviewed
• [Journal Article] Polymorphism near the Interleukin-28B gene and anti-hepatitis C viral response. (2013)
  • Author(s): Asahina Y, Nakagawa M, Kakinuma S, Watanabe M.
  • Journal Title: J Clin Transl Hepatol Volume: 1 Pages: 39-44
  • Peer Reviewed
• [Journal Article] Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C. (2013)
  • 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, Ochanomizu Liver Conference Study Group
  • Journal Title: Hepatol Int Volume: 7(1) Issue: 1 Pages: 153-161
  • DOI: 10.1007/s12072-012-9363-6
  • Peer Reviewed
• [Journal Article] Wnt5a Signaling Mediates Biliary Differentiation of Fetal Hepatic Stem/Progenitor Cells (2013)
  • Author(s): Kakinuma S, Kiyohashi K, Kamiya A, Sakamoto N, Nitta S, Yamanaka H, YoshinoK, Fujiki J, Murakawa M, Kusano-Kitazume A, Shimizu H, Okamoto R, Azuma S, Nakagawa M, Asahina Y, Tanimizu N, Kikuchi A, Nakauchi H, and *WatanabeM
  • Journal Title: Hepatology Volume: (in press) Issue: 6 Pages: 2502-2513
  • DOI: 10.1002/hep.26293
  • Peer Reviewed
• [Journal Article] α-fetoprotein levels afterinterferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C (2013)
  • Author(s): Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M,Izumi N
  • Journal Title: Hepatology Volume: (in press) Issue: 4 Pages: 1253-1262
  • DOI: 10.1002/hep.26442
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [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] 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) Issue: 3 Pages: 1315-23
  • DOI: 10.1128/aac.05764-11
  • Peer Reviewed / Open Access
• [Journal Article] Age and total ribavirin dose are independent predictors of relapse after interferon therapy in chronic hepatitis C revealed by data mining analysis (2012)
  • Author(s): Masayuki Kurosaki
  • Journal Title: Antiviral Therapy Volume: 17(1) Issue: 1 Pages: 35-43
  • DOI: 10.3851/imp1923
  • Peer Reviewed
• [Presentation] Matrix Metalloproteinase-14 regulates the maturation of fetal hepatic stem/progenitor cells in mice (2014)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Azuma S, Asahina Y, Watanabe M
  • Organizer: The 65th Annual Meeting of American Association for the Study of Liver Diseases（AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston（USA）
  • Year and Date: 2014-11-08 – 2014-11-11
• [Presentation] Matrix Metalloproteinase-14 controls differentiation of fetal hepatic stem/progenitor cells (2014)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Azuma S, Asahina Y, Watanabe M
  • Organizer: Japan Digesive Disease Week 2014
  • Place of Presentation: ポートピアホテル（神戸）
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] 肝幹・前駆細胞におけるCalmodulin-dependent protein kinase II活性化動態の解析 (2014)
  • Author(s): 後藤文男, 柿沼 晴, 大谷賢志, 紙谷聡英, 東 正新, 朝比奈靖浩, 渡辺 守
  • Organizer: 第21回肝細胞研究会
  • Place of Presentation: 東京医科歯科大学（東京）
  • Year and Date: 2014-06-27 – 2014-06-28
• [Presentation] Matrix Metalloproteinase-14による肝幹/前駆細胞分化の調節 (2014)
  • Author(s): 大谷賢志, 柿沼 晴, 後藤文男, 紙谷聡英, 新田沙由梨, 東 正新, 中川美奈, 朝比奈靖浩, 坂本直哉, 中内啓光, 渡辺 守
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] Wnt5a-CaMK2経路による肝幹/前駆細胞の分化調節機構 (2013)
  • Author(s): 柿沼 晴、幾世橋 佳、紙谷聡英、新田沙由梨、東正新、中川美奈、朝比奈靖浩、坂本直哉、中内啓光、渡辺 守
  • Organizer: JDDW 2013 第17回日本肝臓学会大会
  • Place of Presentation: 東京（グランドプリンスホテル新高輪）
• [Presentation] 高齢者C型肝炎におけるウイルス排除を目指した治療の有効性と安全性 (2013)
  • Author(s): 柿沼 晴、朝比奈靖浩、渡辺守
  • Organizer: JDDW 2013 第17回日本肝臓学会大会
  • Place of Presentation: 東京（グランドプリンスホテル新高輪）
• [Presentation] Wnt5a-CaMK2経路による肝幹/前駆細胞の胆管分化の調節機構 (2013)
  • Author(s): 柿沼晴、幾世橋佳、山中秀人、紙谷聡英、新田沙由梨、藤木純子、吉野耕平、中川美奈、東正新、坂本直哉、朝比奈靖浩、中内啓光、渡辺守
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京（京王プラザホテル）
• [Presentation] Non-canonical Wnt 経路による肝幹/前駆細胞の増殖/分化の調節
  • Author(s): 柿沼晴
  • Organizer: 第16回日本肝臓学会大会（JDDW2012）
  • Place of Presentation: 神戸
• [Presentation] Matrix Metalloproteinase-2の肝線維化過程における機能の解析
  • Author(s): 柿沼晴
  • Organizer: 第39回日本肝臓学会東部会
  • Place of Presentation: 東京
• [Presentation] 肝線維化の形成におけるMatrix Metalloproteinase-2の機能的意義
  • Author(s): 柿沼晴
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] Impaired IL28B gene induction and poor IL28B promoter activity influenced by the IL28B minor allele are closely associated with a null response to interferon in chronic hepatitis C patients
  • Author(s): Asahina Y, Kakinuma S, et al.
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Book] 内科:肝疾患における再生医療の展望 (2014)
  • Author(s): 柿沼 晴
  • Total Pages: 4
  • Publisher: 南江堂
• [Book] 消化器内科ーNon-canonical Wnt経路による肝幹/前駆細胞の増殖/分化の調節 (2013)
  • Author(s): 柿沼 晴、幾世橋 佳、渡辺 守
  • Total Pages: 5
  • Publisher: 科学評論社
• [Book] 肝幹細胞を用いた細胞移植治療（肝胆膵・分著） (2012)
  • Author(s): 柿沼 晴、他
  • Total Pages: 196
  • Publisher: アークメディア