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<p>In mammals, the postnatal increase in cardiac workload coincides with the loss of cardiomyocyte proliferative capacity, rendering adult cardiomyocytes permanently post-mitotic. Whether reducing load can restore regenerative potential in the adult heart remains unknown. Here we use a heterotopic heart transplantation model, in which the donor heart is vascularized but nonpumping, to show that mechanical unloading induces adult cardiomyocyte proliferation, revealed by Ki67-based and MADM (mosaic analysis with double markers) lineage tracing. Applying heterotopic transplantation to infarcted hearts to achieve mechanical unloading similarly promoted regeneration within peri-infarct regions. Single-nucleus RNA sequencing of unloaded hearts identified enhanced epicardial–cardiomyocyte communication via the NRG1–ERBB4–STAT3 axis. Epicardial <i>Nrg1</i> deletion blocked STAT3 activation and cardiomyocyte proliferation. CUT&amp;Tag revealed STAT3 directly upregulates <i>H6pd</i> in cardiomyocytes, boosting pentose phosphate pathway activity to supply nucleotides and reducing equivalents for proliferation. These findings delineate a mechanotransductive pathway linking epicardial signals to cardiomyocyte cell-cycle re-entry, providing a framework for leveraging unloading to promote cardiac regeneration.</p>

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Mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1–ERBB4 signaling

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Chenyu Jiang,
  • Tianyu Liu,
  • Zihao Dai,
  • Li Xiang,
  • Yifan Zhu,
  • Xingliang Zhou,
  • Xu Huang,
  • Yi Shen,
  • Jian Liu,
  • Yuxi Ji,
  • Lin Cheng,
  • Fang Yu,
  • Yi Yan,
  • Bei Feng,
  • Tuo Pan,
  • Jinhai Chen,
  • Yu Nie,
  • Hao Zhang,
  • Yiwei Liu

摘要

In mammals, the postnatal increase in cardiac workload coincides with the loss of cardiomyocyte proliferative capacity, rendering adult cardiomyocytes permanently post-mitotic. Whether reducing load can restore regenerative potential in the adult heart remains unknown. Here we use a heterotopic heart transplantation model, in which the donor heart is vascularized but nonpumping, to show that mechanical unloading induces adult cardiomyocyte proliferation, revealed by Ki67-based and MADM (mosaic analysis with double markers) lineage tracing. Applying heterotopic transplantation to infarcted hearts to achieve mechanical unloading similarly promoted regeneration within peri-infarct regions. Single-nucleus RNA sequencing of unloaded hearts identified enhanced epicardial–cardiomyocyte communication via the NRG1–ERBB4–STAT3 axis. Epicardial Nrg1 deletion blocked STAT3 activation and cardiomyocyte proliferation. CUT&Tag revealed STAT3 directly upregulates H6pd in cardiomyocytes, boosting pentose phosphate pathway activity to supply nucleotides and reducing equivalents for proliferation. These findings delineate a mechanotransductive pathway linking epicardial signals to cardiomyocyte cell-cycle re-entry, providing a framework for leveraging unloading to promote cardiac regeneration.