In the adult mammalian heart, cardiac myocyte renewal is rare1, 2 and insufficient to restore normal pump function after significant myocardial damage. Recent studies, however, suggest that zebrafish hearts3–5 and neonatal mouse hearts6 can regenerate after injury through enhanced cardiac myocyte proliferation. In mice, this restorative potential is lost shortly after birth. 6 In this issue of Circulation Research, Porrello et al identify the microRNA (miR)-15 family of miRs as potential mediators of the postnatal loss of proliferative potential. 7

Most (if not all) adult mammalian cardiac myocytes permanently exit the cell cycle and do not proliferate even when challenged by injury or stress. Scientists have long sought to understand the mechanisms that prevent cardiac myocyte cell cycle reentry and to overcome these blocks to generate new functional myocytes. 8 Experimental approaches in the past have included manipulation of direct cell cycle regulators such as cyclins and cyclin-dependent kinase inhibitors and regulation of myofibril disassembly, which is thought to be necessary for the mature cardiac myocyte to undergo cell division (cytokinesis). 9 Excitement and enthusiasm for seeking a deeper understanding of this phenomenon have been enhanced by the discovery that adult zebrafish hearts can regenerate even after significant injury4 and by the more recent observation by Porrello et al that newborn mouse hearts can also regenerate. 6 These findings indicate that functional cardiac myocytes, with contractile sarcomeres and myofibrils, are able to reenter the cell cycle and undergo cytokinesis to generate new myocytes. Importantly, this capacity is largely lost during the first week of postnatal life, suggesting that epigenetic changes during that time period alter the myocyte response to injury. Indeed, dramatic changes in gene expression occur shortly after birth as the fetal gene program is silenced and adult isoforms of contractile proteins, calcium transporters, and metabolic regulators are expressed. 10 In rodents, most cardiac myocytes undergo 1 postnatal round of DNA synthesis without cytokinesis, resulting in binucleation and subsequent cell cycle arrest, usually at G0/G1. 11 Altered response to injury, large-scale changes in gene expression, and uncoupling of cytokinesis from karyokinesis (nuclear division) that