PTMA controls cardiomyocyte proliferation and cardiac repair by enhancing STAT3 acetylation
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 <i>Ptma</i> in cardiomyocytes impaired neonatal heart regeneration. AAV9-mediated overexpression of <i>Ptma</i> 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.
Authors
- Xiangjie Li (ORCID: https://orcid.org/0000-0002-9600-8984)
- Yixun Li (ORCID: https://orcid.org/0000-0003-2193-6126)
- Chenying Xiang
- Huiling Cao (ORCID: https://orcid.org/0000-0002-7728-1774)
- Weijing Liu (ORCID: https://orcid.org/0000-0003-0593-5983)
- Yu Nie (ORCID: https://orcid.org/0000-0002-8744-0046)
- 正 石橋 (ORCID: https://orcid.org/0000-0003-0103-2576)
- Jianqiu Pei (ORCID: https://orcid.org/0000-0002-7935-0884)
- Ning Liu (ORCID: https://orcid.org/0000-0002-2108-9476)
- Jue Wang (ORCID: https://orcid.org/0000-0001-6843-9771)
- Xuan He (ORCID: https://orcid.org/0000-0002-5505-8416)
- Nan Jiang (ORCID: https://orcid.org/0000-0002-8849-7976)
- Yangyang Gao (ORCID: https://orcid.org/0009-0004-1483-2374)
- Y. Xie (ORCID: https://orcid.org/0000-0002-9040-0969)
Institutions
- Xi'an International Studies University (CN)
- Capital Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Medical Center Hospital (US)
- Xi'an Medical University (CN)
- Xi’an International University (CN)
- Nanchong Central Hospital (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1126/sciadv.adt9446
- Citations
- 3
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 2.42