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Dev Cell. 2018 Feb 26;44(4):433-446.e7. doi: 10.1016/j.devcel.2018.01.021.

Myocardial Polyploidization Creates a Barrier to Heart Regeneration in Zebrafish.

Author information

1
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
2
The Krannert Institute of Cardiology, the Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, IN 46202, USA.
3
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: cburns6@mgh.harvard.edu.
4
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address: gburns@cvrc.mgh.harvard.edu.

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.

KEYWORDS:

cardiomyocyte; cardiomyocyte proliferation; heart regeneration; polyploidization; zebrafish

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PMID:
29486195
PMCID:
PMC5830170
DOI:
10.1016/j.devcel.2018.01.021
[Indexed for MEDLINE]
Free PMC Article

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