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<p>The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and polyploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that cell-autonomous&#xa0;PIDDosome&#xa0;loss causes an increase in nuclear and cellular CM ploidy. Increased ploidy does not affect cardiac structure nor function in early adulthood, but correlates with a modest reduction in cardiac performance in aged mice. PIDDosome-imposed polyploidy control commences at postnatal day 7 (P7), reaching a plateau by P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on induction of <i>p21/Cdkn1a</i>, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.</p><p></p>

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The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • M. Leone,
  • N. Kinz,
  • F. Eichin,
  • D. Obwegs,
  • V. C. Sladky,
  • V. Z. Braun,
  • R. Hirschberger,
  • D. Rizzotto,
  • L. Englmaier,
  • C. Manzl,
  • K. Moos,
  • J. Mergner,
  • P. Giansanti,
  • N. Martinez-Garcia,
  • M. M. Marques,
  • E. D. Jacotot,
  • L. Eblahed,
  • R. Yousif,
  • M. K. Wright,
  • D. Dawood,
  • L. S. Maupome,
  • C. Savko,
  • M. Boerries,
  • M. A. Sussman,
  • A. Villunger

摘要

The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and polyploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that cell-autonomous PIDDosome loss causes an increase in nuclear and cellular CM ploidy. Increased ploidy does not affect cardiac structure nor function in early adulthood, but correlates with a modest reduction in cardiac performance in aged mice. PIDDosome-imposed polyploidy control commences at postnatal day 7 (P7), reaching a plateau by P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on induction of p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.