2023 Fiscal Year Final Research Report

Development of human iPS cell-derived hepatocyte organoids as models of liver fibrosis and carcinoma

Research Project

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Project/Area Number	21H02896
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 53010:Gastroenterology-related
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, 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) 岡本隆一東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50451935)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	肝細胞 / iPS細胞 / オルガノイド / 肝細胞癌 / 再生医療
Outline of Final Research Achievements	The objectives of this research grant program were to establish a novel culture method for human iPS cell-derived hepatocyte organoids (iPS-Hep Organoid), and to construct a new liver disease model that can reproduce a part of hepatocellular carcinogenesis using human iPS cells whose target genes were modified by genome editing. As a result of examining a lot of culture conditions, we have developed a new method for generating human iPS-Hep Organoids that can be cultured for more than six months, which maintained characters of hepatic lineages. Next, we established human iPS cell lines that mimic a part of the hepatocellular carcinogenesis that occurs in chronic liver disease caused by the hepatitis B virus infection. The established iPS cells were differentiated into hepatic lineage generated and were analyzed. Such cells exhibited several features of hepatocellular carcinoma, and the precise molecular mechanism underlying was clarified.
Free Research Field	肝臓病学
Academic Significance and Societal Importance of the Research Achievements	本研究計画では、これまでは困難であった、ヒトiPS細胞由来肝細胞オルガノイド<iPS-Hep Organoid>の新規培養法を確立することに成功した。これによって、病気の際に肝細胞がうける様々な刺激により、どのように変化するかを長期間にわたって解析することが可能になった。本研究は、今はまだ根治的な治療法がない、肝硬変の新しい治療法開発に結びつくことが期待される。また肝細胞癌発癌の一部を再現するヒトiPS細胞の研究では、正常な細胞がどのように癌形質を獲得してゆくかを明らかにしつつある。そのメカニズムを知ることで、肝細胞がんに対する新しい分子標的を開発に繋がってゆく可能性がある。