Conserved microRNA program as key to mammalian cardiac regeneration: insights from zebrafish.

Abstract

The capacity of the adult mammalian heart to repair itself after injury is limited. In contrast, lower vertebrates such as Zebrafish can completely regenerate the organ after damage. A recent article from Aguirre et al1 in Cell Stem Cell shows that this difference is because of a microRNA program that is active in Zebrafish but silent in mammals. Crucially, reactivation of this dormant microRNA program in the murine heart induces regeneration of the myocardium. The adult mammalian heart possesses a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult.2 This is, in part, because of the low proliferative capacity of adult cardiomyocytes. Myocardial injury increases cardiomyocyte proliferation3; however, it is clearly insufficient to completely regenerate the myocardium, and many strategies to enhance the weak regenerative response of the mammalian heart to injury are currently under investigation. The neonatal mammalian heart potentially possesses a higher regenerative capacity compared with the adult organ. In one study, cardiac regeneration was observed in 1-day-old neonatal mice after partial surgical resection.4 Using genetic fate mapping techniques, the researchers showed that the regenerated myocardium originated from preexisting cardiomyocytes proliferating in response to injury.4 This regenerative capacity was lost by day 7.4 Other studies have also pointed to an enhanced natural regenerative capacity in neonatal mice.5,6 In contrast to mammals, lower vertebrates such as Zebrafish retain the ability to regenerate their hearts throughout life. In the case of the Zebrafish, this natural ability is particularly robust as complete cardiac regeneration has been observed even when ≈20% of the ventricular myocardium was removed.7 The proliferation of partially dedifferentiated cardiomyocytes underlies this process.8 Specifically, cardiomyocytes that are adjacent to the site of injury break down their sarcomeres, express the embryonic cardiogenesis gene Gata4, and enter …