Over the last decade a number

Over the last decade, a number of studies have proposed that the adult mammalian heart is not a terminally differentiated organ and is capable of turning over cardiomyocytes throughout life and following injury (Porrello and Olson, 2010). The most compelling evidence for this radical concept comes from radiocarbon dating experiments of nuclear DNA from heart samples that were exposed to nuclear fallout during weapons testing during the Cold War. These studies revealed that human cardiomyocytes turn over at a low rate of about 1% per year, which declines to 0.5% per year after the age of 50 (Bergmann et al., 2009). The cellular source of these regenerated cardiomyocytes in humans remains controversial, but a recent study in mice suggests that cardimoyocyte proliferation is most likely the dominant cellular mechanism (Senyo et al., 2013). Therefore, cardiomyocyte proliferation appears to be the primary natural mechanism for cardiomyocyte replenishment in highly regenerative organisms such as zebrafish and neonatal mice, as well as in less regenerative adult mammals. As such, understanding the mechanisms that govern cardiomyocyte proliferation during development and regeneration is paramount.
Cardiomyocyte proliferative signaling during neonatal heart development and regeneration As with many regenerative processes, cardiac regeneration in adult zebrafish involves the re-engagement of a number of growth factor signaling pathways that guide embryonic heart development, including the Igf, RA, Fgf and Notch signaling pathways (Fig. 2) (Huang et al., 2013; Kikuchi et al., 2011a; Lepilina et al., 2006; Zhao et al., 2014). However, in contrast to the capacity of these growth factors to stimulate myocardial proliferation during embryogenesis and early neonatal life in mammals, adult mammalian cardiomyocytes do not readily re-enter the Bindarit in response to similar developmental cues (Shioi et al., 2000; Collesi et al., 2008). Even in response to mitogens that are associated with some degree of adult cardiomyocyte proliferation, such as neuregulin, periostin, FGF in combination with a p38α MAPK inhibitor or inhibition of glycogen synthase kinase 3β, only a very low percentage of adult cardiomyocytes re-enter the cell cycle and complete cytokinesis, and this effect is thought to be restricted to the mononucleated subset of cardiomyocytes in rodents (Bersell et al., 2009; Engel et al., 2006; Engel et al., 2005; Kuhn et al., 2007; Tseng et al., 2006). Interestingly, even in the highly proliferative adult newt heart, only ~30% of binucleated cardiomyocytes were able to undergo cytokinesis, suggesting that binucleation is a major barrier to cardiomyocyte mitotic progression (Matz et al., 1998). As such, recent attention has focused on unraveling the underlying molecular events that silence the genetic networks required for cardiomyocyte proliferation during neonatal life.
Endogenous cardiac stem and progenitor cells Resident tissue stem and progenitor cell populations reside in most adult tissues and contribute to cellular homeostasis and repair throughout life. In the heart, several cardiac stem/progenitor populations have been identified at different developmental stages including the embryonic, neonatal and adult heart. Cardiac stem cells have been identified on the basis of cell surface marker expression (e.g. c-kit, Sca-1), transcription factor expression (e.g. Isl-1), physiological dye efflux properties and propensity to form multicellular clusters (e.g. cardiospheres, colony-forming units-fibroblasts (cfu-f)) (Beltrami et al., 2003; Chong et al., 2011; Oh et al., 2003; Jackson et al., 2001; Messina et al., 2004; Laugwitz et al., 2005). Given that mammalian cardiomyocyte renewal is extremely limited in the adult heart following infarction, it is important to determine whether cardiac stem cells might play an important role in more highly regenerative organisms, such as zebrafish and neonatal mice.