
본 연구는 CHIR99021과 A-485라는 두 가지 화합물의 조합(2C)이 인간 배아 줄기세포(hESC) 유래 심근세포를 심장 재생 세포(RCC)로 효과적으로 전환시키는 것을 보여주며, 이는 손상된 심장을 복구하기 위한 유망한 재생 전략을 제시합니다.


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Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, i.e., regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell (hESC)-derived TNNT2+ CMs in vitro , as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells (ECs), and smooth muscle cells (SMCs). Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo . Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.

### Competing Interest Statement

The authors have declared no competing interest.

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