Study on establishment of experimental animal model for chimeric liver with hepatitis C virus infection using induced hepatocyte-like cells

• Project/Area Number: 24590959
• 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: AZUMA Seishin 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, 寄付講座講師 (30372444) ; ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄付講座教授 (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): SAKAMOTO Naoya 北海道大学, 医学研究科, 教授 (10334418)
• 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: 移植 / 発生・分化 / 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 hepatic stem/progenitor cells. Based on the results of above-mentioned analysis, we tried to establish the mouse model of chimeric liver using directly reprogrammed hepatocyte-like cells. We found that Wnt5a and Wnt5a-related molecules control the biliary differentiation of hepatic stem/progenitor cells. Next, our data indicated that MMP14 and MMP14-related molecules 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 drug discovery for viral hepatitis using mouse model of cell-transplanted chimeric liver in future.

Research Products

• [Journal Article] Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse 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: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: Hepatology 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] 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] 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] 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, Azuma S, Kakinuma S, Watanabe M, et al.
  • Journal Title: Hepatol Int Volume: in press
  • Peer Reviewed
• [Journal Article] 多血性肝細胞癌の検出能に関するGd-EOB-DTPA造影MRIとCTAP/CTHAとの比較検討 (2013)
  • Author(s): 東 正新、柿沼 晴、渡辺 守、他
  • Journal Title: 医学と薬学 Volume: 69 Pages: 64-66
• [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
• [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Calmodulindependent 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] Intermediate HCC に対するIVR を併用したRFA 治療の意義の検討 (2014)
  • Author(s): 東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第５０回日本肝癌研究会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-06-05 – 2014-06-06
• [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] Comparison between Gd-EOB-DTPA MRI and CTHA/CTAP for detection of hypervascular hepatocellular carcinoma: efficacy of diffusion weighted image and hepatobiliary phase. (2013)
  • Author(s): Azmua S, Asahina Y, Sakurai Y, Ootani S, Yamanaka H, Kawai F, Fujiki J, Kitazume A, Murakawa M, Nakagawa M, Kakinuma S, Watanabe M.
  • Organizer: 22nd Conference of the Asian Pacific Association for the Study of the Liver.
  • Place of Presentation: Singapore (Singapore)
• [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] 肝細胞癌診断におけるMRI拡散強調画像の有用性の検討 (2013)
  • Author(s): 東 正新、朝比奈靖浩、後藤文男、大谷賢志、谷口未樹、河合富貴子、藤木純子、村川美也子、小野塚泉、新田沙由梨、北詰晶子、櫻井幸、中川美奈、柿沼晴、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] 肝細胞癌診断における拡散強調画像の有用性 (2013)
  • Author(s): 東正新、朝比奈靖浩、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] 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] Impaired IL28B gene induction and expression of IFNγ4 are closely associated with a non-response to interferon-based therapy in chronic hepatitis C patients (2013)
  • Author(s): Asahina Y, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Watanabe M
  • Organizer: The 64rd Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2013)
  • Place of Presentation: ワシントン(USA)
• [Presentation] EOB-MRIおよびAngio-CTによる多血性肝細胞癌に関する検討
  • Author(s): 東 正新、柿沼 晴、渡辺 守、他
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] ４個以上の多発肝細胞癌に対するラジオ波熱焼灼術の適応と意義の検討
  • Author(s): 東 正新、渡辺 守、他
  • Organizer: 第３９回日本肝臓学会東部会
  • Place of Presentation: 東京
• [Presentation] Wnt5a-CaMK2経路によるマウス肝幹/前駆細胞の胆管形成の調節
  • Author(s): 幾世橋 佳、柿沼 晴、東 正新、渡辺 守、他
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] Antiviral effetcts and action mechanisms of novel N-(morpholine-4-carbonyloxy) amidine compounds against hepatitis C virus
  • Author(s): Kusano-Kitazume A, Kakinuma S, Azuma S, Watanabe M, et al.
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [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, Azuma S, Watanabe M, et al.
  • Organizer: 63rd Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston