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Nat Genet. 2017 Sep;49(9):1346-1353. doi: 10.1038/ng.3929. Epub 2017 Aug 7.

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration.

Author information

1
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
2
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
3
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
5
Program of Developmental Biology and Regenerative Medicine, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
6
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
7
Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
8
Developmental Neuroscience Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
9
Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Abstract

Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

PMID:
28783163
PMCID:
PMC5736145
DOI:
10.1038/ng.3929
[Indexed for MEDLINE]
Free PMC Article

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