Chen Yu, Li Aoli, Liu Aijie, Zheng Wei, Fan Haishi, Zhang Jingwei, Huang Chenwen
Department of Clinical Research Centre, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Wholesomebio Technology Co., Ltd, Shanghai, China.
Commun Med (Lond). 2025 Jul 1;5(1):266. doi: 10.1038/s43856-025-00963-y.
Cell therapy, particularly using cardiomyocytes, shows significant promise for treating heart failure. Direct reprogramming of somatic cells into cardiomyocytes using small molecules is advantageous due to its efficiency and cost-effectiveness.
Human urine-derived cells (hUCs) were transdifferentiated into functional cardiomyocyte-like cells (hCiCMs) using a cocktail of 15 small molecules under xeno-free conditions. Various Characterizations were performed, including immunofluorescence, transmission electron microscopy (TEM), qPCR, single-cell RNA sequencing, patch-clamp recordings, and intracellular Ca² measurements. The therapeutic potential was tested in both mouse and porcine models of myocardial infarction (MI).
Reprogramming efficiency achieves 15.08% on day 30, with purity reaching 96.67% on day 60. hCiCMs display cardiomyocyte markers, sarcomeric structures, and abundant mitochondria. Electrophysiological analysis confirms ventricular-like action potentials and regular calcium transients. Single-cell RNA sequencing reveals cardiomyocyte subpopulations resembling 13-week embryonic human heart cells, with gene ontology analysis indicating successful maturation. In the MI model, hCiCM transplantation improves cardiac function, increasing ejection fraction and fractional shortening while reducing fibrosis.
This study demonstrates the successful reprogramming of hUCs into functional hCiCMs using small molecules under xeno-free conditions, offering a scalable, autologous cell source for cardiac repair with significant potential for regenerative therapies.
细胞疗法，尤其是使用心肌细胞，在治疗心力衰竭方面显示出巨大潜力。利用小分子将体细胞直接重编程为心肌细胞具有效率高和成本效益好的优势。
在无血清条件下，使用15种小分子鸡尾酒将人尿液来源细胞（hUCs）转分化为功能性心肌样细胞（hCiCMs）。进行了各种表征，包括免疫荧光、透射电子显微镜（TEM）、qPCR、单细胞RNA测序、膜片钳记录和细胞内Ca²测量。在小鼠和猪心肌梗死（MI）模型中测试了其治疗潜力。
在第30天重编程效率达到15.08%，在第60天纯度达到96.67%。hCiCMs表现出心肌细胞标志物、肌节结构和丰富的线粒体。电生理分析证实了类似心室的动作电位和规则的钙瞬变。单细胞RNA测序揭示了类似于13周龄人类胚胎心脏细胞的心肌细胞亚群，基因本体分析表明成功成熟。在MI模型中，hCiCM移植改善了心脏功能，增加了射血分数和缩短分数，同时减少了纤维化。
本研究证明了在无血清条件下使用小分子成功地将hUCs重编程为功能性hCiCMs，为心脏修复提供了一种可扩展的自体细胞来源，在再生治疗方面具有巨大潜力。
