The development of human iPSC derived proliferative progenitors for the effectively massive production of liver organoid

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22946
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0905:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: NIE YUNZHONG 東京大学, 医科学研究所, 助教 (00831330)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: Stem cell / Liver regenration / Liver organoid / Liver reconsturction

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.

Free Research Field

再生医学

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。