基于人源细胞的心肌细胞可塑性及其应用研究

心肌梗死是危害国民健康与经济的重要心血管事件，损伤心肌的修复与再生直接关系到疾病的预后。目前，外源性补充丢失的心肌细胞或激活内源性心肌细胞增殖被视为潜在的治疗手段。然而，人多能干细胞来源心肌细胞（hPSC-CM）的不成熟特性，以及成人心肌细胞几乎不具备增殖能力的自然属性，使得这些潜在手段在心肌修复与再生中的应用充满挑战。针对这个问题，在突破了成人原代心肌细胞（hPCM）分离培养与单细胞分析等技术瓶颈的基础上，我们拟系统解析hPCM与hiPSC-CM的功能特征与高分辨分子图谱，揭示人心肌细胞可塑性调节的分子阀门，从而能够在体外操纵心肌细胞命运，促进外源性心肌细胞的成熟与内源性心肌细胞的增殖，并最终在心肌梗死小鼠模型中验证潜在治疗策略的有效性。本研究通过解答人心肌细胞可塑性这一核心问题，深入探讨细胞表型转化的分子机制与调控网络，为心肌梗死的治疗提供理论参考。

Myocardial infarction is a critical cardiovascular event threatening national health and economy. Repair and regeneration of the damaged myocardium directly affects disease prognosis. Currently, exogenous supply of cardiomyocytes and triggering endogenous cardiomyocyte proliferation are both considered potentially effective treatment measures. However, the immature characteristics of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), as well as the lack of proliferative potential of fully differentiated adult human cardiomyocytes, are hampering their application in cardiac repair and regeneration. To this end, upon overcoming the technical barriers of isolation, culture, and single-cell analysis of adult human primary cardiomyocytes (hPCMs), we propose to systematically illustrate the functional and molecular profiles of hPCMs and hiPSC-CMs at high resolution, with which we will uncover the nodes of cardiomyocyte plasticity control. We will further apply these strategies to induce maturation of hiPSC-CMs, and elicit pro-proliferative responses in adult hPCMs, and finally validate the effect of such schemes in a mouse model of myocardial infarction. This study aims to address the central question of cardiomyocyte plasticity, to uncover the molecular underpinnings and the regulatory network of cardiomyocyte phenotype conversion, and to provide data support for the treatment of myocardial infarction.