Analyses of molecular mechanisms underlying differentiation and proliferation of hepatic stem/progenitor cells for development of novel cell transplantation models

• Project/Area Number: 15K08988
• 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, 大学院医歯学総合研究科, 寄附講座准教授 (30372444)
• Co-Investigator(Kenkyū-buntansha): 朝比奈 靖浩 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) ; 渡辺 守 (渡邉 守) 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, 医学部, 准教授 (30321904)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 再生医学 / 発生・分化 / 細胞移植 / 肝疾患治療 / iPS細胞

Outline of Final Research Achievements

Investigators of this research project have studied on the molecular mechanisms underlying differentiation and proliferation of primary hepatic stem/progenitor cells purified by cell surface molecules and therapeutic efficacy of transplantation using hepatic stem/progenitor cells.
Our data demonstrated that MT1-MMP and MT1-MMP-related signaling promote luminal formation of bile ducts derived from fetal hepatic stem/progenitor cells, and that they negatively regulate differentiation of such cells into mature hepatocytes in association with modulation of EGF-signaling pathway. Our data also showed that BMP-4 signaling negatively regulates proliferation of primary 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] Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. (2017)
  • Author(s): Nagata H, Nakagawa M, Asahina Y, Sato A, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Azuma S, Kakinuma S, Nouchi T, Sakai H, Tomita M, Watanabe M
  • Journal Title: J Hepatol Volume: 67 Issue: 5 Pages: 933-939
  • DOI: 10.1016/j.jhep.2017.05.028
  • Peer Reviewed / Open Access
• [Journal Article] ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin. (2017)
  • Author(s): Murakawa M, Asahina Y, Nagata H, Nakagawa M, Kakinuma S, Nitta S, Kawai-Kitahata F, Otani S, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Sato A, Itsui Y, Azuma S, Nouchi T, Furumoto Y, Asano T, Chuganji Y, Tohda S, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 11 Pages: 1212-1218
  • DOI: 10.1111/hepr.12867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatic IFNL4 expression is associated with non-response to interferonbased therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients. (2017)
  • Author(s): Murakawa M, Asahina Y, Kawai-Kitahata F, Nakagawa M, Nitta S, Otani S, Nagata H, Kaneko S, Asano Y, Tsunoda T, Miyoshi M, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Iijima S, Tsuchiya K, Izumi N, Tohda S, Watanabe M.
  • Journal Title: J Med Virol Volume: in press Issue: 7 Pages: 1241-1247
  • DOI: 10.1002/jmv.24763
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human induced pluripotent stem cell-derived hepatic cell line as a new model for host interaction with hepatitis B virus. (2016)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Nitta S, Asano Y, Nagata H, Otani S, Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Iwamoto M, Watashi K, Wakita T, Sugiyama M, Mizokami M, Shimotohno K, Watanabe M.
  • Journal Title: Sci Rep Volume: ６ Issue: 1 Pages: 29358-29358
  • DOI: 10.1038/srep29358
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bone Morphogenetic Protein-4 Modulates Proliferation and Terminal Differentiation of Fetal Hepatic Stem/Progenitor Cells. (2016)
  • Author(s): Goto F, Kakinuma S, Miyoshi M, Tsunoda T, Kaneko S, Sato A, Asano Y, Otani S, Azuma S, Nagata H, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Nakagawa M, Asahina Y, Watanabe M.
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 9 Pages: 941-952
  • DOI: 10.1111/hepr.12823
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. (2016)
  • Author(s): Kawai-Kitahata F, Asahina Y, Tanaka S, Kakinuma S, Murakawa M, Sayuri Nitta S, Watanabe T, Otani S, Taniguchi M, Goto F, Nagata H, Kaneko S, Tasaka-Fujita M, Nishimura-Sakurai Y, Azuma S, Itsui Y, Nakagawa M, Tanabe M, Takano S, Fukasawa M, Sakamoto M, Maekawa S, Enomoto N, Watanabe M.
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 5 Pages: 473-486
  • DOI: 10.1007/s00535-015-1126-4
  • Peer Reviewed
• [Journal Article] Serial measurement of Wisteria floribunda agglutinin positive Mac-2-binding protein is useful for predicting liver fibrosis and the development of hepatocellular carcinoma in chronic hepatitis C patients treated with IFN-based and IFN-free therapy. (2016)
  • Author(s): Nagata H, Nakagawa M, Nishimura-Sakurai Y, Asano Y, Tsunoda T, Miyoshi M, Kaneko S, Goto F, Otani S, Kawai-Kitahata F, Murakawa M, Nitta S, Itsui Y, Seishin Azuma S, Kakinuma S, Tojo N, Tohda T, Asahina Y, Watanabe M, the Ochanomizu Liver Conference Study Group.
  • Journal Title: Hepatol Int Volume: 10 Issue: 6 Pages: 956-964
  • DOI: 10.1007/s12072-016-9754-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Matrix Metalloproteinase-14 Mediates Formation of Bile Ducts and Hepatic Maturation of Fetal Hepatic Progenitor Cells. (2016)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Miyoshi M, Tsunoda T, Asano Y, Kawai-Kitahata F, Nitta S, Nakata T, Okamoto R, Itsui Y, Nakagawa M, Azuma S, Asahina Y, Yamaguchi T, Koshikawa N, Seiki M, Nakauchi H, Watanabe M.
  • Journal Title: Biochem Biophys Res Commun Volume: 469 Issue: 4 Pages: 1062-1068
  • DOI: 10.1016/j.bbrc.2015.12.105
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficacy of additional radiofrequency ablation after transcatheter arterial chemoembolization for intermediate hepatocellular carcinoma. (2016)
  • Author(s): Azuma S, Asahina Y, Nishimura-Sakurai Y, Kakinuma S, Kaneko S, Nagata H, Goto F, Ootani S, Kawai-Kitahata F, Taniguchi M, Murakawa M, Watanabe T, Tasaka-Fujita M, Itsui Y, Nakagawa M, Watanabe M.
  • Journal Title: Heptol Res Volume: 46 Issue: 4 Pages: 312-9
  • DOI: 10.1111/hepr.12566
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of IFN resistance in newly established genotype 1b HCV cell culture system. (2016)
  • Author(s): Taniguchi M, Tasaka-Fujita M, Nakagawa M, Watanabe T, Kawai-Kitahata F, Otani S, Goto F, Nagata H, Kaneko S, Nitta S, Murakawa M, Nishimura-Sakurai Y, Azuma S, Itsui Y, Mori K, Yagi S, Kakinuma S, Asahina Y, Watanabe M.
  • Journal Title: J Clin Transl Hepatol Volume: 4 Issue: 1 Pages: 5-11
  • DOI: 10.14218/jcth.2015.00047
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Presentation] ゲノム編集ヒトiPS 細胞による疾患モデルを用いた先天性肝線維症の病態メカニズムの解析 (2017)
  • Author(s): 角田知之、柿沼 晴、渡辺 守
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] ヒトiPS 細胞由来肝細胞系譜細胞を用いたB 型肝炎ウイルス感染への宿主自然免疫応答の解析 (2017)
  • Author(s): 金子 俊、柿沼 晴、朝比奈靖浩
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] ゲノム編集ヒトiPS 細胞由来胆管様細胞を利用した先天性肝線維症の病態解明 (2017)
  • Author(s): 柿沼 晴、角田知之、朝比奈靖浩、渡辺 守、他
  • Organizer: 第24回肝細胞研究会
• [Presentation] ヒトiPS細胞由来間葉系譜細胞とヒトiPS 細胞由来肝前駆様細胞との細胞間相互作用の解析 (2017)
  • Author(s): 三好正人、柿沼 晴、渡辺 守
  • Organizer: JDDW 2017（第21回日本肝臓学会大会）
• [Presentation] A novel culture model for coinfection of hepatitis B and hepatitis C viruses using human induced pluripotent stem cell-derived hepatic cells for analyses of changes in host-innate immune responses (2017)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Watanabe M, et al.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] Evaluation of an early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C patients treated with All-Oral DAAs - propensity score-matched analysis of a prospective database - (2017)
  • Author(s): Nakagawa M, Asahina Y, Kakinuma S, Watanabe M, et al.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] Matrix Metalloproteinase-14 の肝前駆細胞分化における機能解析 (2016)
  • Author(s): 大谷賢志、柿沼 晴、渡辺 守
  • Organizer: 第102回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
• [Presentation] 肝幹/前駆細胞におけるBone Morphogenetic Protein-4 の機能解析 (2016)
  • Author(s): 後藤文男、柿沼 晴、大谷賢志、角田知之、三好正人、浅野 侑、金子 俊、井津井靖浩、中川美奈、東正新、朝比奈靖浩、渡辺 守
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県千葉市）
• [Presentation] Bone Morphogenetic Protein-4 による肝幹/ 前駆細胞の増殖と終末分化の調節機構 (2016)
  • Author(s): 柿沼 晴、後藤文男、角田知之、三好正人、大谷賢志、浅野 侑、金子 俊、東 正新、渡辺 守
  • Organizer: 第23回肝細胞研究会
  • Place of Presentation: 大阪大学中之島センター（大阪府大阪市）
• [Presentation] HBV 排除にむけたヒトiPS 細胞由来肝細胞系譜細胞を用いた培養系の開発 (2016)
  • Author(s): 金子 俊、柿沼 晴、朝比奈靖浩
  • Organizer: JDDW2016（第24回日本消化器関連学会週間）
  • Place of Presentation: 神戸コンベンションセンター（兵庫県神戸市）
• [Presentation] Genetically modified human induced pluripotent stem cell-derived hepatic progenitor-like cell lines as a model for interaction between hepatitis B virus and host cells. (2016)
  • Author(s): Shun Kaneko, Sei Kakinuma, Yasuhiro Asahina, Akihide Kamiya, Masato Miyoshi, Tomoyuki Tsunoda, Sayuri Nitta, Ayako Sato, Yu Asano, Hiroko Nagata, Satoshi Otani, Fukiko Kawai-Kitahata, Miyako Murakawa, Yasuhiro Itsui, Mina Nakagawa, Seishin Azuma, Mamoru Watanabe.
  • Organizer: AASLD The Liver Meeting 2016
  • Place of Presentation: Boston（USA）
  • Int'l Joint Research
• [Presentation] Human induced pluripotent stem cell-derived hepatic progenitor-like cells and hepatocyte-like cells as a model for interaction between hepatitis B virus and host cells. (2015)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya S, Nitta S, Tsunoda T, Miyoshi M, Nagata H, Goto F, Otani S, Murakawa M, Kitahata-Kawai F, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
  • Organizer: The American Association for the Study of Liver Diseases, The Liver Meeting 2015
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [Presentation] Matrix Metalloproteinase-14を介した肝幹/前駆細胞の分化調節機構 (2015)
  • Author(s): 柿沼 晴、大谷賢志、渡辺 守
  • Organizer: JDDW 2015
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2015-10-08
• [Presentation] Matrix Metalloproteinase-14 による肝幹/前駆細胞の分化・成熟化の調節 (2015)
  • Author(s): 柿沼 晴、大谷賢志、紙谷聡英、後藤文男、金子 俊、東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第22回肝細胞研究会
  • Place of Presentation: 米子コンベンションセンター（島根県米子市）
  • Year and Date: 2015-06-04
• [Presentation] 肝幹/前駆細胞におけるMatrix Metalloproteinase-14による分化調節機構の解析 (2015)
  • Author(s): 大谷賢志、柿沼 晴、後藤文男、紙谷聡英、櫻井 幸、井津井康浩、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51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2015-05-21
• [Presentation] Matrix Metalloproteinase (MMP)-14 regulates the differentiation of hepatic stem/progenitor cells. (2015)
  • Author(s): Otani S, Kakinuma S, Watanabe M.
  • Organizer: The 3rd Japanese Society of Gastroenterology International Topic Conference
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2015-04-24
  • Int'l Joint Research