Genetic lineage tracing in human epidermal organoids reveals the evolutionary adaptedness of epidermal stem cells to environmental factors

2020 Fiscal Year Final Research Report

• Project/Area Number: 20K22624
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0701:Biology at molecular to cellular levels, and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Shimokawa Mariko 東京医科歯科大学, 難治疾患研究所, プロジェクト助教 (70627017)
• Project Period (FY): 2020-09-11 – 2021-03-31
• Keywords: 表皮オルガノイド / 皮膚老化 / 変異獲得細胞クローン拡大

Outline of Final Research Achievements

It has been reported that long-period UV-exposed normal skin cells spread clonally with maintaining physiological function, after acquiring human skin cancer mutation. The mechanism of the clone expansion is unclear, although it is expected that normal epidermal cells adapt to the tumor-promoting environment by selecting mutant clones, In this study, we focus on the association with stem cell competition as a system that the epidermal stem cells maintain the epidermal tissue homeostasis. Using the mouse epidermal organoid culture method, a system was created for observing the interaction between mutant cells and neighboring cells by observing the epidermal stem cell dynamics in the mutant-introduced organoid. This result enables the application of genetic analysis of aging to human cells, which has remained in the mouse model, and is expected to be a major advance in mutual understanding of human aging and cancer.

Free Research Field

皮膚老化

Academic Significance and Societal Importance of the Research Achievements

既存のマウス表皮オルガノイドの培養条件を改善することで、短期間で生体内表皮の組織構造を再現することを可能にし、表皮オルガノイド幹細胞解析系を確立した。さらに当研究室で保有している条件的に遺伝子変異を導入することが可能なマウスを用い、条件的変異導入可能なオルガノイド作製にも成功した。このオルガノイドが組織構造を再現した後変異獲得幹細胞の動態観察にも成功した。この成果は、マウスにとどまっていた老化の遺伝学的解析をマウス細胞における解析、およびヒト細胞への応用を可能にするもので、ヒト老化およびがんの相互理解への大きな進歩と期待される。