PTMA controls cardiomyocyte proliferation and cardiac repair by enhancing STAT3 acetylation

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-23 DOI:10.1126/sciadv.adt9446

Ning Liu, Jianqiu Pei, Yifan Xie, He Xuan, Nan Jiang, Jue Wang, Yangyang Gao, Yixun Li, Xiangjie Li, Weijing Liu, Chenying Xiang, Zheng Qiao, Haiping Cao, Yu Nie

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Abstract

The adult mammalian heart has limited regenerative capacity due to the low proliferative ability of cardiomyocytes, whereas embryonic cardiomyocytes exhibit robust proliferative potential. Using single-cell RNA sequencing of embryonic hearts, we identified prothymosin α (PTMA) as a key factor driving cardiomyocyte proliferation. Overexpression of PTMA in primary mouse and rat cardiomyocytes significantly promoted cardiomyocyte proliferation and similarly enhanced proliferation in human iPSC–derived cardiomyocytes. Conditional knockout of Ptma in cardiomyocytes impaired neonatal heart regeneration. AAV9-mediated overexpression of Ptma extended the neonatal proliferative window and showed therapeutic promise for enhancing adult heart regeneration. Mechanistically, PTMA interacted with MBD3, inhibiting its deacetylation activity within the MBD3/HDAC1 NuRD complex. This inhibition increased STAT3 acetylation, which positively regulated STAT3 phosphorylation and activation of its target genes. These findings establish PTMA as a critical regulator of heart regeneration and suggest its potential as a therapeutic target for ischemic myocardial injury.

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PTMA通过增强STAT3乙酰化控制心肌细胞增殖和心脏修复

由于心肌细胞的增殖能力较低，成年哺乳动物心脏的再生能力有限，而胚胎心肌细胞则表现出强大的增殖潜力。利用胚胎心脏的单细胞RNA测序，我们发现胸腺肽原α (PTMA)是驱动心肌细胞增殖的关键因素。PTMA在小鼠和大鼠原代心肌细胞中的过表达显著促进了心肌细胞的增殖，并同样增强了人ipsc来源的心肌细胞的增殖。心肌细胞条件敲除Ptma损害新生儿心脏再生。aav9介导的Ptma过表达延长了新生儿的增殖窗口期，并显示出增强成人心脏再生的治疗前景。机制上，PTMA与MBD3相互作用，抑制MBD3/HDAC1 NuRD复合物内的去乙酰化活性。这种抑制增加了STAT3乙酰化，从而正向调节STAT3磷酸化及其靶基因的激活。这些发现表明PTMA是心脏再生的关键调节因子，并提示其作为缺血性心肌损伤的治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.