Elucidation of cardiomyocyte dedifferentiation and proliferation mechanisms

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03683
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Kikuchi Kazu 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (10638240)
• Co-Investigator(Kenkyū-buntansha): 大谷 健太郎 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (50470191)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 心筋再生 / 心筋細胞 / 脱分化 / 増殖 / 転写因子 / ゼブラフィッシュ / マウス / 心不全

Outline of Final Research Achievements

We performed a genome-wide analysis of Klf1 binding sites and found that most Klf1 binding sites are enriched in distal enhancer regions, which induces a global reduction in chromatin accessibility. Motif enrichment analysis revealed that the binding sites for the core cardiac transcription factors (Gata4, Nkx2-5, Mef2) are significantly enriched in the reduced accessibility regions, indicating that Klf1 induces cardiomyocyte dedifferentiation by suppressing cardiac gene regulatory network controlled by the core cardiac transcription factors. Klf1 also upregulates the expression of diverse cell cycle genes with a simultaneous downregulation of the mitochondrial respiration pathway, which enables cardiomyocytes to proliferate with reduced oxidative stress. We generated transgenic mouse lines and observed that Klf1 induction also leads to the increase of cardiomyocyte proliferation and cardiac size, and further analysis of these mouse lines is underway.

Free Research Field

再生生物学

Academic Significance and Societal Importance of the Research Achievements

申請者が見出したKlf1経路は既知のHippo-Yap経路やErbb2経路などとは異なる、全く新しい心筋再生誘導機構である。これまで心筋細胞増殖の誘導は主に増殖促進機構の解明を中心に行われてきたが、本研究によりKlf1が心筋細胞の脱分化と代謝リプログラミングにおいても重要な機能を果たすことが明らかとなった。本研究によるKlf1機能の解明は、ヒト心筋細胞を増殖不能から増殖可能状態へと転換する新規医療技術の開発に大きく貢献することが期待される。