Muscling up the heart: a preadolescent cardiomyocyte proliferation contributes to heart growth.

Abstract

A recent study from Naqvi et al1 in Cell shows that in mice during preadolescence, cardiomyocytes undergo a burst of proliferation that is related to a thyroid hormone surge. This study challenges the conventional model of the timing of terminal differentiation and provides a direction for further mechanistic research on cardiomyocyte proliferation and differentiation. In mice and rats, cardiomyocytes transition from the mono- to the binucleated phenotype in the first week of life.2,3 It is commonly thought that this indicates the transition from the proliferative state to permanent cell cycle exit. However, the precise molecular-genetic mechanisms of terminal differentiation are unknown. Reversing this process and stimulating the proliferation of terminally differentiated cardiomyocytes is a century-old challenge and considered by many scientists as a Holy Grail. It has been thought that heart growth after birth is exclusively through enlargement (hypertrophy) but not proliferation of cardiomyocytes.4 However, several lines of evidence challenge the absoluteness of the notion that new cardiomyocytes are not generated after birth. First, Poss et al5 found that adult zebrafish can completely regenerate heart defects by increasing cardiomyocyte proliferation, indicating that differentiated adult cardiomyocyte phenotypes exist that can re-enter the cell cycle. Second, we have demonstrated that human hearts show cardiomyocyte proliferation until the second decade of life.6 Third, it was demonstrated that some adult mammalian cardiomyocytes can be stimulated to re-enter the cell cycle.7–11 Fourth, we have demonstrated that neuregulin-stimulated cell cycle re-entry happens predominantly in the mononucleated portion.10 The causative connection between endogenous cardiomyocyte proliferation and myocardial regeneration was established in zebrafish5 and neonatal mice,12 although part of the latter has been challenged recently.13 Several reports indicate that stimulating cardiomyocyte proliferation in adult mammals improves myocardial repair.10,11 Thus, controlling postnatal …