| Project/Area Number |
21K16377
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 55010:General surgery and pediatric surgery-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NIE YUNZHONG 東京大学, 医科学研究所, 助教 (00831330)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | hiPSC / Mini liver tissue / tissue structure / NASH / Kupffer cell / Hepatic stellate cells / LSEC / liver / disease modeling |
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| Outline of Research at the Start |
This project aims to generate a mini liver tissue from human induced pluripotent stem cells (hiPSCs) by step-wisely mimicking the liver organogenesis. In this three-dimensional (3D) liver tissue, we aim to recapitulate the sinusoid structure among hepatocytes, maintain the quiescent characteristic of hepatic stellate cells (HSCs), and create a natural immune environment with Kupffer cells (KCs). Moreover, we will investigate the usefulness of this mini liver tissue in modeling the progression of injury-induced liver diseases and finding potential treatments for these diseases.
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| Outline of Final Research Achievements |
This project generated mini liver tissue with hiPSCs derived Hepatoblast, fetal hepatic stellate cells (HSC), endothelial progenitors, and monocytes. Within 10 days of culture, these cells organized and matured into tissue-like structures with an increased expression of hepatic function genes and secretion of Albumin. Moreover, lineage tracing and genetic analysis showed that endothelial progenitors gradually developed into sinusoidal endothelial networks, HSC maintained their quiescent characteristics, and monocytes were differentiated into Kupffer cells. The typical liver-specific ultrastructure was also observed in the mini-liver tissues. When treating these liver tissues with free fatty acids, we detected a marked lipid accumulation, resulting in an enhanced immune response, activation of HSC, and hepatic injury. These results suggested that we generated a hiPSC-derived mini liver tissue for studying development and treatment of human nonalcoholic steatohepatitis.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究開発しているヒトミニ肝組織にはヒトの肝臓に非常に近い細胞構成や組織構造を持つことが確認された。 In vitroでヒト機能肝臓再構築基礎研究において画期的な進歩である。近年にNASHの発症率は急速に増加し、現代社会において深刻な健康問題となっている。本ヒトミニ肝組織の活用により、NASHの病態生理や病態進行をIn vitroで再現され、NASHの疾患メカニズムや新たな治療法の開発に向けた重要な一歩が踏み出された。これにより、将来的には効果的な予防策や治療法の開発が可能となり、NASH患者の生活の質の向上や医療負担の軽減につながることが期待される。
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