| Project/Area Number |
20K22946
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0905:Surgery of the organs maintaining homeostasis and related fields
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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) |
2020-09-11 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Stem cell / Liver regenration / Liver organoid / Liver reconsturction / liver organoid / hiPSC / progenitor / liver disease / progenitor cells |
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| Outline of Research at the Start |
We aim to generate hiPSC derived proliferative progenitors that exist in the fetal liver. These progenitors derived LOs will be much close to the fetal liver's characteristic that will be beneficial to improve the effectiveness of treatment. Since these progenitors acquire the proliferative capacity, the human-scale production of LOs will be much more costless and accessible, and the transplantation safety of LOs will also be significantly improved. Therefore, the progenitors derived LOs will provide a promising, safe, and effective therapeutic strategy for liver disease.
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| Outline of Final Research Achievements |
We previously found that liver organoids (LOs) derived from hiPSC might be a potential alternative for liver transplantation. This project aimed to generate hiPSC derived proliferative liver progenitors and establish an efficient LO production system. With the optimization of culture conditions, we have generated proliferative Hepatoblast and fetal hepatic stellate cells, which could be proliferated 10^15 times and 10^8 times, respectively. We also transplanted these proliferative progenitors into immunodeficiency mice and did not observe tumor formation at the transplant sites. Moreover, we found the transplanted Hepatoblast could repopulate in the liver of chronic liver injury models and mature into functional hepatocytes. To further improve the production efficiency, we developed a matrix- and 3D microwell-free method to generate LOs with these progenitors, which exhibited an improved hepatic function compared with the conventional method derived LOs.
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| Academic Significance and Societal Importance of the Research Achievements |
末期肝疾患を治療するための移植可能なドナーの持続的な深刻な不足のために、新しい移植可能なヒト肝臓の開発が緊急に必要とされている。ヒトiPS細胞由来の肝臓オルガノイド（LO）は肝移植の潜在的な代替手段である。効率的な低安全で低コストのLO作製法の開発は臨床への応用における最重要なステップである。この研究では、増殖性前駆細胞に基づいてLO作製基盤を構築した。増殖性前駆細胞の技術は、未分化のiPSの排除と細胞分化誘導コストの削減に有益と考えられ、より安全、低コスト、高機能のLOを製造が促進されることが期待される。
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