Zhou Wei, He Kezhang, Wang Chiyin, Wang Pengqi, Wang Dan, Wang Bowen, Geng Han, Lian Hong, Ma Tianhua, Nie Yu, Ding Sheng
School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, China.
Elife. 2024 Dec 9;13:RP93405. doi: 10.7554/eLife.93405.
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, that is, 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-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, and smooth muscle cells. 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.
与一些低等生物不同，成年哺乳动物缺乏通过心肌细胞（CMs）去分化为具有再生能力的细胞来再生受损心脏的能力。开发诱导这类在哺乳动物中天然不存在的、具有增殖和分化为CMs潜力的细胞（即再生心脏细胞，RCCs）的条件，将为心脏再生研究提供新的见解和工具。在本研究中，我们证明了CHIR99021和A - 485这两种化合物的组合（2C）能在体外有效地从人胚胎干细胞衍生的TNNT2 CMs诱导产生RCCs，谱系追踪实验证明了这一点。功能分析表明，这些RCCs表达广泛的心脏发生基因，并有分化为功能性CMs、内皮细胞和平滑肌细胞的潜力。重要的是，在新生大鼠CMs的体外和体内实验中也观察到了类似结果。值得注意的是，在成年小鼠心脏中给予2C能显著提高心肌梗死后的存活率并改善心脏功能。从机制上讲，CHIR99021对于RCC发育所必需基因的转录和表观遗传激活至关重要，而A - 485主要抑制CMs中的H3K27Ac，特别是H3K9Ac。它们的协同作用增强了RCC基因上的这些修饰，促进了从CMs向RCCs的转变。因此，我们的研究结果证明了从内源性CMs药理学诱导RCCs的可行性，并揭示了其机制，这可能为修复受损心脏提供一种有前景的再生策略。
