Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration
Open Access
- 7 August 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 49 (9), 1346-1353
- https://doi.org/10.1038/ng.3929
Abstract
Henry Sucov and colleagues demonstrate substantial natural variation in the capacity of the mouse heart to regenerate after injury and link this to the prevalence of mononuclear diploid cardiomyocytes. They identify Tnni3k as one gene that contributes to the observed variation and validate its role through mouse knockout and zebrafish overexpression studies. 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.Keywords
This publication has 52 references indexed in Scilit:
- Cardiomyocytes in Young Infants With Congenital Heart Disease: a Three-Month Window of ProliferationScientific Reports, 2016
- Circulating Cells Contribute to Cardiomyocyte Regeneration After InjuryCirculation Research, 2015
- TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathyHuman Molecular Genetics, 2014
- Contribution of Bone Marrow-Derived Hematopoietic Stem/Progenitor Cells to the Generation of Donor-Marker+ Cardiomyocytes In VivoPLOS ONE, 2013
- Cardiomyocyte proliferation contributes to heart growth in young humansProceedings of the National Academy of Sciences of the United States of America, 2013
- Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferationNature, 2010
- Tnni3k Modifies Disease Progression in Murine Models of CardiomyopathyPLoS Genetics, 2009
- Adolescent Feline Heart Contains a Population of Small, Proliferative Ventricular Myocytes With Immature Physiological PropertiesCirculation Research, 2007
- Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin IJournal of Molecular Medicine, 2003
- Cardiac-Specific Overexpression of Cyclin-Dependent Kinase 2 Increases Smaller Mononuclear CardiomyocytesCirculation Research, 2001