Cardiomyocyte maturation and proliferation is a flip coin.

Cardiac regeneration offers a promising approach to treating ischemic heart disease. Accumulating evidence indicates that maturation limits the proliferative capacity of the adult myocardium. During cardiac development, cardiomyocytes (CMs) undergo genetic reprogramming, leading to maturation characterized by polyploid CMs, increased sarcomere rigidity, and metabolic reprogramming that prepares the heart for efficient, sustained blood pumping capacity throughout life. This maturation process also coincides with cell cycle exit in adult CMs and forms a barrier to replenishing the CM loss after ischemic injury. Over recent decades, studies have shown that forced induction of adult CM proliferation involves reversion to an immature state. Therefore, understanding the changes that occur during maturation is essential to flip the coin to enable the induction of CM proliferation in adulthood, with potential therapeutic applications for ischemic heart disease. This review discusses the relationship between postnatal CM maturation and CM proliferation.