Mammalian heart is considered postmitotic with limited cardiomyocyte (CM) turnover during lifetime of an individual [1]. Adult CMs are typically unable to complete the cell cycle and respond to growth signals by hypertrophy or incomplete cytokinesis resulting in binucleation and/or polyploidization, considered to be major hurdles in CM proliferation and regeneration [2]. Ensuing years have seen a tremendous effort to delineate CM cell cycle and develop strategies that promote cell cycle reentry and CM mediated regeneration of the heart following injury. Success and effectiveness of these strategies is debatable, and existence of a true CM based regenerative strategy that drives meaningful increases in CM numbers in the heart augmenting cardiac structure and function following injury remains elusive. Can the heart repair itself or in essence adult CMs can be a viable target for generating de novo, mature and functionally competent CMs after myocardial injury?

The answer may lie in how the heart regulates proliferative and regenerative responses during early postnatal cardiac stages. Fetal or neonatal CMs are known to actively proliferate and populate the heart in response cardiac tissue growth. Cellular and molecular signature of developmental CMs is unique and has provided blueprint for several strategies that have employed reactivation of developmental signaling for CM proliferation (Fig. 1). The following sections will provide a perspective on how reactivation of developmental signaling affects CM cell cycle, cardiac repair and regenerative process in the heart following injury.