Turning Back the Cardiac Regenerative Clock: Lessons From the Neonate

Ahmed I. Mahmoud, Enzo R. Porrello

The adult mammalian heart has an extremely limited capacity for regeneration. As a consequence, ischemic heart disease remains the leading cause of death in the developed world, and the heart continues to be a major focal point for regenerative medicine. Understanding innate mechanisms of heart regeneration is important and may provide a blueprint for clinical translation. For example, urodele amphibians and teleost fish can mount an endogenous regenerative response following multiple forms of cardiac injury, and this regenerative response appears to be mediated through proliferation of pre-existing cardiomyocytes. How and why mammals have lost the capacity for heart regeneration since the divergence from teleost fish more than 450 million years ago has been a major unresolved question in the field. Recent studies in mice indicate that the mammalian heart possesses significant regenerative potential during embryonic and neonatal life, but this regenerative capacity is lost rapidly after birth. This review focuses on mechanisms of heart regeneration in neonatal mice, with a particular emphasis on similarities and differences with the zebrafish model. Recent advances in our understanding of the molecular mechanisms of postnatal heart maturation and regenerative arrest are also highlighted. The possibility of recapitulating ontogenetically and phylogenetically ancient mechanisms of cardiac regeneration in the adult human heart represents an exciting new frontier in cardiology.