Composing the human fetal liver niche for HSC using human iPSC-liver organoids.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K15753
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38030:Applied biochemistry-related
• Research Institution: Kyoto University (2020-2021); Kansai Medical University (2019)
• Principal Investigator: Sumide Keisuke 京都大学, iPS細胞研究所, 特定研究員 (20826458)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ヒト造血幹細胞 / 肝オルガノイド / 胎児造血

Outline of Final Research Achievements

Human hematopoietic stem cells (HSCs) give rise to almost blood cells. HSCs have been reported to proliferate most actively in the fetal liver. However, the mechanism of that has not been elucidated. On the other hand, it is difficult to collect a large amount of fetal liver tissue for research use because of the ethical reasons. In this study, to mimic the environment of the human fetal liver HSC niche, I tried to make-up the fetal-liver-like organoids composed by human iPSC-derived hepatoblasts, stellate cell-like cells and sinusoidal endothelium-like cells. Then, human cord blood HSCs were included or transplanted into the organoids. As the results, fetal hematopoietic-like active erythroid differentiation was observed in HSC coculture system with hepatoblasts and the organoid. On the other hand, less proliferation of HSC was observed. These data suggest that the elements of fetal liver environments are still lacking in the organoids.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ヒト造血幹細胞（HSC）特性を維持したまま体外で維持培養または増殖培養できれば、難病に対する遺伝子治療や献血に頼らない輸血用製剤の開発等、待望される数々の技術を実現化する。現在、数種報告のあるHSC増幅技術は、その機序に不明点が多く、HSCが活発に増幅する胎児肝環境における細胞同士の関係性を理解する必要があった。本研究では、ヒトiPS細胞由来肝芽が胎児造血に特徴的な赤血球分化の促進を認めたものの、現時点ではHSC自身の増殖は認められなかった。一方で、ヒトHSCは肝細胞の成熟に寄与する示唆を得た。本研究成果は、HSC増殖を支持する、より高度なヒト肝オルガノイド構築法界へ津への寄与が期待される。