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Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 2017 Sep;49(9):1346-1353

Date

08/08/2017

Pubmed ID

28783163

Pubmed Central ID

PMC5736145

DOI

10.1038/ng.3929

Scopus ID

2-s2.0-85028707436 (requires institutional sign-in at Scopus site)   243 Citations

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.

Author List

Patterson M, Barske L, Van Handel B, Rau CD, Gan P, Sharma A, Parikh S, Denholtz M, Huang Y, Yamaguchi Y, Shen H, Allayee H, Crump JG, Force TI, Lien CL, Makita T, Lusis AJ, Kumar SR, Sucov HM

Author

Michaela Patterson PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Cells, Cultured
Diploidy
Gene Expression Profiling
Heart
Immunoblotting
In Situ Hybridization, Fluorescence
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Confocal
Myocardium
Myocytes, Cardiac
Protein Kinases
Regeneration
Zebrafish