Progressive cardiac disease can lead to heart failure in adults due to permanent loss of cardiomyocytes. In contrast, the early aged mammalian neonatal heart in rodents and, most recently, porcine models exhibits significant tissue renewal of beating cells after injury (2, 8, 11). Despite the insufficient regenerative response of the adult heart to disease and damage, an emerging consensus supports the proliferative capacity of a subpopulation(s) of cardiomyocytes during development into mammalian adulthood (2, 6). The nature of cardiomyocyte proliferation has been informed by study of prenatal cardiac development, interspecies comparisons with lower vertebrates, surgical injury, and the neonatal cardiac regenerative mouse model. Neonatal mice restore damaged ventricular tissue by a variety of insults (apical resection or vessel ligation) over several weeks by transient proliferation of cardiomyocytes, similar to phenomena in zebrafish. This robust regenerative response in early aged neonates is suppressed just a few days after birth, and injured hearts follow an adult phenotype of permanent fibrosis and loss of cardiac physiology (2, 8, 11). Deep genome sequencing has identified modulators of the tissue regeneration and cardiomyocyte proliferation activity, including gene programming downstream of environmental factors, such as oxygen tension and paracrine signaling from the epicardium and immune cell activity. For example, expression patterns of microRNAs (miR-590, miR-199a, and miR15) and immune cell secretome (M2 and regulatory T cells) indicate developmental remodeling of the epige-netic and transcriptome landscape is correlated with postnatal silencing of fetal pathways associated with cardiac regeneration
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