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PTMA通过增强STAT3乙酰化来控制心肌细胞增殖和心脏修复。

PTMA controls cardiomyocyte proliferation and cardiac repair by enhancing STAT3 acetylation.

作者信息

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

机构信息

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.

出版信息

Sci Adv. 2025 May 23;11(21):eadt9446. doi: 10.1126/sciadv.adt9446.

DOI:10.1126/sciadv.adt9446
PMID:40408476
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12101487/
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 in cardiomyocytes impaired neonatal heart regeneration. AAV9-mediated overexpression of 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.

摘要

成年哺乳动物心脏由于心肌细胞增殖能力低而具有有限的再生能力，而胚胎心肌细胞则表现出强大的增殖潜力。通过对胚胎心脏进行单细胞RNA测序，我们确定前胸腺素α（PTMA）是驱动心肌细胞增殖的关键因素。在原代小鼠和大鼠心肌细胞中过表达PTMA可显著促进心肌细胞增殖，在人诱导多能干细胞衍生的心肌细胞中同样增强增殖。心肌细胞中PTMA的条件性敲除损害了新生心脏的再生。腺相关病毒9介导的PTMA过表达延长了新生期增殖窗口，并显示出增强成年心脏再生的治疗前景。从机制上讲，PTMA与MBD3相互作用，抑制其在MBD3/HDAC1 NuRD复合物中的去乙酰化活性。这种抑制增加了STAT3的乙酰化，从而正向调节STAT3的磷酸化及其靶基因的激活。这些发现确立了PTMA作为心脏再生的关键调节因子，并表明其作为缺血性心肌损伤治疗靶点的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/f62431894a60/sciadv.adt9446-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/071ec8fb93aa/sciadv.adt9446-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/f62431894a60/sciadv.adt9446-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/8a33d9f13be1/sciadv.adt9446-f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/fda3e07c939b/sciadv.adt9446-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/50cec6b7df55/sciadv.adt9446-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/4ebddf1f3f8f/sciadv.adt9446-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/1afb1d1360eb/sciadv.adt9446-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/0a257038a458/sciadv.adt9446-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/071ec8fb93aa/sciadv.adt9446-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d035/12101487/f62431894a60/sciadv.adt9446-f10.jpg

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本文引用的文献

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The activation of LBH-CRYAB signaling promotes cardiac protection against I/R injury by inhibiting apoptosis and ferroptosis.LBH-CRYAB信号通路的激活通过抑制细胞凋亡和铁死亡来促进心脏对缺血/再灌注损伤的保护作用。
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Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair.
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SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B.SIRT2通过使STAT3去乙酰化来对抗灵长类动物心脏衰老，而STAT3去乙酰化会使CDKN2B沉默。
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