2021 Fiscal Year Final Research Report
Mechanism of intercellular signaling in steatohepatitis using human liver organoids
Project/Area Number |
19K16536
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 49010:Pathological biochemistry-related
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Yoneyama Yosuke 東京医科歯科大学, 統合研究機構, 助教 (10748289)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | 脂肪性肝炎 / ヒトiPS細胞 / オルガノイド / 細胞間シグナル |
Outline of Final Research Achievements |
Non-alcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver failure, which is associated with multicellular pathogenesis including macrophage-mediated inflammation and hepatic stellate cell-mediated fibrosis. In this study, we established a novel steatohepatitis model in human iPSC-derived multicellular liver organoids that recapitulate the inflammatory and fibrogenic responses. By using this organoid model, we investigated intercellular signaling, leading to the identification of the potential anti-fibrotic signaling factor and its cellular and molecular mechanisms. This study will delineate the multicellular mechanisms of the signaling pathways alleviating NASH fibrosis, and will contribute to the drug development to attenuate the fibrosis in human NASH.
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Free Research Field |
医化学
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Academic Significance and Societal Importance of the Research Achievements |
本研究の成果により、パラクライン因子や細胞間相互作用を加味したヒトNASHにおける肝炎や線維化に関する病態進展の一端が細胞・分子レベルで解明される。将来的に、臨床病態への外挿性が担保されたオルガノイドスクリーニング基盤を通じて、本研究で見出された因子を標的とする治療有効性の高いシーズ化合物の導出が期待される。ヒトiPS細胞由来オルガノイドモデルを活用することで、環境要因等の交絡因子を排除した形で患者固有の病態再現や治療標的の導出、バイオマーカー開発を進める戦略は、肝臓以外の肺や腎臓などの重要臓器の線維症研究にも大きな波及効果を生み出すと考えられる。
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