Myocardial Polyploidization Creates a Barrier to Heart Regeneration in Zebrafish

Juan Manuel González-Rosa, Michka Sharpe, Dorothy Field, Mark H. Soonpaa, Loren J. Field, Caroline E. Burns, C. Geoffrey Burns

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Correlative evidence suggests that polyploidization of heart muscle, which occurs naturally in post-natal mammals, creates a barrier to heart regeneration. Here, we move beyond a correlation by demonstrating that experimental polyploidization of zebrafish cardiomyocytes is sufficient to suppress their proliferative potential during regeneration. Initially, we determined that zebrafish myocardium becomes susceptible to polyploidization upon transient cytokinesis inhibition mediated by dominant-negative Ect2. Using a transgenic strategy, we generated adult animals containing mosaic hearts composed of differentially labeled diploid and polyploid-enriched cardiomyocyte populations. Diploid cardiomyocytes outcompeted their polyploid neighbors in producing regenerated heart muscle. Moreover, hearts composed of equivalent proportions of diploid and polyploid cardiomyocytes failed to regenerate altogether, demonstrating that a critical percentage of diploid cardiomyocytes is required to achieve heart regeneration. Our data identify cardiomyocyte polyploidization as a barrier to heart regeneration and suggest that mobilizing rare diploid cardiomyocytes in the human heart will improve its regenerative capacity. It remains unclear why certain non-mammalian species efficiently regenerate their hearts while mammals fail in this endeavor. González-Rosa et al. demonstrate that simply increasing the DNA content of the highly regenerative zebrafish myocardium, to more closely resemble that in mammals, is sufficient to dampen cardiomyocyte proliferative capacity and organ regeneration.

Original languageEnglish (US)
Pages (from-to)433-446.e7
JournalDevelopmental Cell
Volume44
Issue number4
DOIs
StatePublished - Feb 26 2018

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Keywords

  • cardiomyocyte
  • cardiomyocyte proliferation
  • heart regeneration
  • polyploidization
  • zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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