Research on molecular mechanisms underlying terminal differentiation of hepatic stem/progenitor cells via non-canonical Wnt signaling pathways

• Project/Area Number: 15K08989
• 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, 講師 (10376783)
• Co-Investigator(Kenkyū-buntansha): 柿沼 晴 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) ; 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)
• 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: 幹細胞 / 発生・分化 / 再生医学 / 肝疾患治療 / シグナル調節

Outline of Final Research Achievements

This research project has investigated on the molecular mechanisms underlying terminal differentiation of hepatic stem/progenitor cells via non-canonical Wnt signaling pathways.
Screening using transcriptome analysis revealed that Wnt5a signaling is associated with Bone morphogenetic protein-4 (BMP-4) signaling pathway in hepatic stem/progenitor cells. BMP-4-mediated signaling suppressed the proliferation and biliary luminal formation of hepatic stem/progenitor cells. BMP-4 signaling promoted the hepatic maturation of hepatic stem/progenitor cells. Moreover, Wnt5a and BMP-4 coordinately suppressed proliferation and cholangiocytic luminal formation of hepatic stem/progenitor cells. Our data also showed that Matrix Metalloproteinase-14-mediated signaling accelerated the biliary luminal formation of hepatic stem/progenitor cells.
These studies can contribute to the progress of regenerative medical science in the field of 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] 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] 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] 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] 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] 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] NAFLD由来肝細胞癌の囲い込みにおける糖尿病性網膜症診断の有用性 (2017)
  • Author(s): 東 正新、朝比奈靖浩、渡辺 守
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] Genetic differences in hepatocellular carcinoma among chronic persistent hepatitis B virus infection with or without viral suppression and prior hepatitis B virus infection (2017)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kakinuma S, Azuma S, Watanabe M, et al.
  • Organizer: EASL The International Liver Congress 2017
  • Int'l Joint Research
• [Presentation] LHX2発現によるヒトiPS 由来間葉系細胞の機能調節 (2017)
  • Author(s): 三好正人、柿沼 晴、東 正新、朝比奈靖浩、渡辺 守、他
  • Organizer: 第24回肝細胞研究会
• [Presentation] Diabetic retinopathy as a risk factor associated with development of hepatocellular carcinoma in non-alcoholic fatty liver disease (2017)
  • Author(s): Azuma S, Asahina Y, Kakinuma S, Azuma K, Watanabe M
  • Organizer: APDW2017
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来肝臓系譜細胞による病態モデルの作成と先天性肝線維症の病態解析 (2017)
  • Author(s): 角田知之、柿沼 晴、東 正新、朝比奈靖浩、渡辺 守、他
  • Organizer: 第54回日本消化器免疫学会総会
• [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, Azuma S, Watanabe M, et al.
  • Organizer: AASLD The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] A new model for studying interaction between hepatitis B virus and host cells derived from human induced pluripotent stem cells. (2016)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Nitta S, Tsunoda T, Miyoshi M, Asano Y, Nagata H , Goto F, Otani S, Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
  • Organizer: EASL, The International Liver Congress 2016
  • Place of Presentation: Barcelona（Spain）
  • Int'l Joint Research
• [Presentation] Intermediate HCCに対する治療戦略 (2016)
  • Author(s): 東 正新、朝比奈靖浩、櫻井 幸、井津井康浩、三好正人、井上恵美、浅野 侑、金子 俊、永田紘子、後藤文男、大谷賢志、北畑富貴子、新田沙由梨、村川美也子、中川美奈、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] BMP-4 による肝幹/前駆細胞の増殖と終末分化の制御機構 (2016)
  • Author(s): 柿沼 晴、後藤文男、大谷賢志、角田知之、三好正人、東 正新、金子 俊、浅野 侑、永田紘子、北畑富貴子、村川美也子、新田沙由梨、井津井康浩、中川美奈、朝比奈靖浩、渡辺 守.
  • 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] 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 A, Nitta S, Tsunoda T, Miyoshi M, Nagata H, Goto F, Otani S, Murakawa M, Kawai-Kitahata F, Itsui Y, Nakagawa M, Azuma S, Watanabe M.
  • Organizer: 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] 2015265372 Intermediate stage以後および肝機能不良の肝癌の治療選択と予後: Intermediate HCCに対する局所治療併用効果の検討 (2015)
  • Author(s): 東 正新, 朝比奈 靖浩, 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: 2015-05-22
• [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] Gene alterations in tert promoter, CTNNB1, and TP53 are closely associated with development and prognosis of hepatocellular carcinoma: comprehensive analyses by next generation sequencing technology. (2015)
  • Author(s): Asahina Y, Kawai-Kitahata F, Kaneko S, Nagata H, Goto F, Otani S, Taniguchi M, Murakawa M, Nitta S, Watanabe T, Tasaka-Fujita M, Nishimura-Sakurai Y, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Tanaka S, Tanabe M, Enomoto N, Watanabe M.
  • Organizer: European Association of the Study of Liver Disease, 50th The International liver congress
  • Place of Presentation: Vienna (Austria)
  • Year and Date: 2015-04-22
  • Int'l Joint Research