Abstract 45: Cardiomyocytes Undergo Division Postnatally to Generate New Cardiomyocytes in Mouse Models of Aging and Cardiac Injury
The dogma of the adult mammalian heart as a post-mitotic organ has recently come under question. Radiolabeled isotope studies have demonstrated that the human heart exhibits a low rate of renewal of cardiomyocytes throughout one’s lifespan. Furthermore, a neonatal mouse can regenerate its ventricle if the apex is resected within the first week of birth. However, the field has yet to clonally address whether cardiomyocytes divide symmetrically upon birth, or if a resident progenitor differentiates into cardiomyocytes. Rather than rely on proxies for cell division (e.g. BrdU incorporation studies), we use genetic mouse models in which cell division results in asymmetric, indelible labeling of the daughter cells (“Mosaic analysis of double markers” (MADM)) to identify which cell type(s) generate cardiomyocytes. We made two triple-transgenic mouse strains: actinCreER;MADMGT/TG and Myh6CreERT2;MADMGT/TG. The former model allows us to identify postnatal cardiogenesis from any cell type, whereas with the latter model we identify postnatal cardiomyocytes that arise from existing alpha-myosin heavy chain-expressing cardiomyocytes. Our studies demonstrate limited symmetric division of cardiomyocytes during normal aging up to six weeks, with a significantly high rate of cardiomyocyte division during the first postnatal week, in both models. The rate of generation of cardiomycoytes is very similar in both models, suggesting that the postnatal cardiomyocyte division accounts for all postnatal cardiomyocyte birth. In the injury model, we provide evidence for cell division in the infarcted heart of a myocardial infarction model, but this rate of division is not greater than in the sham animal, suggesting that the inflammatory environment following an MI does not provide additional pro-mitotic signals. Our data suggests that, as in teleost fish such as zebrafish that demonstrate robust myocardial regeneration even in adulthood, the cell of origin for mammalian postnatal cardiogenesis is a differentiated cell - the cardiomyocyte - rather than a multipotent progenitor cell. It remains to be explored whether all cardiomyocyte are able to divide postnatally or whether this phenomenon is restricted to a subpopulation of cardiomyocytes.
- © 2012 by American Heart Association, Inc.