Generation of mature induced-cardiomyocytes by direct cardiac reprogramming and elucidation of their molecular mechanisms

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17095
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Keio University
• Principal Investigator: Kojima Hidenori 慶應義塾大学, 医学部(信濃町), 共同研究員 (10645766)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 心筋リプログラミング / 再生医療 / 心筋細胞 / 成熟

Outline of Final Research Achievements

In direct cardiac reprogramming, the efficiency of generation of functional induced-cardiomyocytes (iCM), which are fully reprogrammed and exhibit spontaneous contraction, is low and the molecular mechanisms are unclear. These are one of the obstacles to the clinical application of cardiac reprogramming.
We found that the utilization of activated Mef2c promotes the induction of beating mature iCM, which were morphologically, functionally, and transcriptionally similar to mature cardiomyocytes.
Then, we clarified that histone acetyltransferase p300 is involved in the maturation of iCM by active Mef2c. p300 is recruited by active Mef2c to the transcriptional regulatory regions of heart-related genes, evokes epigenetic reprogramming, and cooperates with heart-related factors to promote the maturation of iCM in cardiac reprogramming.

Free Research Field

再生医療

Academic Significance and Societal Importance of the Research Achievements

心筋ダイレクトリプログラミングは心臓病治療の有望な治療法となりうるが、完全にリプログラミングされ自律拍動を呈する機能的なiCMの効率は低く、その分子メカニズムも不明である。これらは臨床応用に向けて障害の一つとなっている。
本研究は、活性型Mef2cにより誘導されたiCMが多角的に成熟であり、その分子メカニズムにp300を介したエピジェネティックなリプログラミングが関与していることを発見した。これらの成果は心筋リプログラミングの臨床応用のみならず、心臓発生や他領域のリプログラミングの分子メカニズムの解明の一助になると思われる。