Cell Reports
Volume 30, Issue 9, 3 March 2020, Pages 3105-3116.e4
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Article
Direct Comparison of Mononucleated and Binucleated Cardiomyocytes Reveals Molecular Mechanisms Underlying Distinct Proliferative Competencies

https://doi.org/10.1016/j.celrep.2020.02.034Get rights and content
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Highlights

  • A FACS-based strategy separates mononucleated and binucleated cardiomyocytes

  • Mononucleated and binucleated cardiomyocytes are transcriptionally distinct

  • Binucleation results in the silencing of E2f transcriptional targets

  • Increased binucleation due to the loss of Ect2 impairs regenerative potential

Summary

The mammalian heart is incapable of regenerating a sufficient number of cardiomyocytes to ameliorate the loss of contractile muscle after acute myocardial injury. Several reports have demonstrated that mononucleated cardiomyocytes are more responsive than are binucleated cardiomyocytes to pro-proliferative stimuli. We have developed a strategy to isolate and characterize highly enriched populations of mononucleated and binucleated cardiomyocytes at various times of development. Our results suggest that an E2f/Rb transcriptional network is central to the divergence of these two populations and that remnants of the differences acquired during the neonatal period remain in adult cardiomyocytes. Moreover, inducing binucleation by genetically blocking the ability of cardiomyocytes to complete cytokinesis leads to a reduction in E2f target gene expression, directly linking the E2f pathway with nucleation. These data identify key molecular differences between mononucleated and binucleated mammalian cardiomyocytes that can be used to leverage cardiomyocyte proliferation for promoting injury repair in the heart.

Keywords

cardiac regeneration
mononucleated
binucleated
cardiomyocyte
proliferation
Rb
E2f
Ect2
heart
development

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