An alternative approach would be to identify successful

An alternative approach would be to identify successful examples of organ regeneration in nature, dissect their mechanisms, and then attempt to apply gained insights to humans via the provision of the appropriate regenerative stimuli. Urodele amphibians and teleosts are well-known examples of animals that possess remarkable regenerative capacity in a variety of structures and organs as adults (Brockes and Kumar, 2008; Poss, 2010). Among these, the zebrafish (Danio rerio) is a relatively new experimental model in regeneration biology, and has been quickly established as the standard for investigating mechanisms of natural organ regeneration, primarily due to its amenability to genetic approaches. Zebrafish are highly regenerative as adults and regrow injured or amputated tissues such as fins (Johnson and Weston, 1995), maxillary barbel (LeClair and Topczewski, 2010), retinae (Vihtelic and Hyde, 2000), optic nerves (Bernhardt et al., 1996), spinal cord (Becker et al., 1997), heart muscle (Poss et al., 2002), Dioscin (Kroehne et al., 2011), hair cells (Ma et al., 2008), pancreas (Moss et al., 2009), liver (Sadler et al., 2007), and kidney (Diep et al., 2011). Although cardiac regeneration and repair have been investigated in other teleost models (Grivas et al., 2014; Ito et al., 2014; Lafontant et al., 2012), zebrafish arguably display the most robust and best characterized cardiac regenerative responses known to date among non-mammalian vertebrate models (Chablais et al., 2011; González-Rosa et al., 2011; Parente et al., 2013; Poss et al., 2002; Schnabel et al., 2011; Wang et al., 2011). This review will summarize recent advances in the field of regenerative medicine and discuss cellular and molecular mechanisms underlying the cardiac regenerative response in zebrafish.
Origins of regenerated myocardium
Regulations by epicardial and endocardial cells
Molecular mechanisms of cardiomyocyte proliferation
Conclusions and perspectives The view of the mammalian heart as a post-mitotic organ with no regenerative capacity has been revised as a result of recent studies. The neonatal mouse heart has been shown to possess robust regenerative capacity during a short window of time after birth (Porrello et al., 2011b). This capacity diminishes within a week, which seems to coincide with binucleation and loss of proliferative capacity of cardiomyocytes (Laflamme and Murry, 2011). In contrast, the majority of cardiomyocytes are mononucleated in the zebrafish heart (Wills et al., 2007). In the adult mouse heart, a small population of mononucleated cardiomyocytes has been shown to proliferate in the presence of growth factor stimulation (Bersell et al., 2009), supporting the notion that mononucleation is a prerequisite for cardiomyocyte proliferation. However, a recent study has reported the surprising finding that both mononucleated and binucleated mouse cardiomyocytes retain robust proliferative capacity beyond the neonatal period, being temporarily reactivated at postnatal day 15, and contributing to a substantial increase in new cardiomyocytes in the preadolescent heart (Naqvi et al., 2014). Significant proliferation of cardiomyocytes does not seem to occur after this period, but it has been recognized that the heart maintains self-renewal capacity at a measurable level throughout life (Bergmann et al., 2009; Senyo et al., 2013). Collectively, these findings illuminate the possibility of reactivating endogenous regenerative capacity in the human heart as a novel therapeutic strategy to treat cardiac diseases. Successful stimulation of endogenous regenerative capacity in injured human hearts will benefit from studies discussed above on the robust regenerative responses observed in the adult zebrafish heart. Previous genetic fate-mapping studies have shown that the zebrafish heart utilizes cardiomyocyte proliferation as the dominant mechanism to regenerate myocardium. Understanding intrinsic and extrinsic molecular signals that control cardiomyocyte proliferation and differentiative quiescence in this model will have direct implications for how regeneration can be stimulated in the injured human heart through cardiomyocyte proliferation. Chemical genetics approaches are an interesting strategy to dissect such mechanisms, which may be facilitated by recently developed transgenic reporter strains in which cardiomyocyte proliferation and regeneration can be monitored in live animals (Chen et al., 2013; Choi et al., 2013). Novel lineage tracing studies have identified several previously unknown sources for regenerating muscle, which will promote further inquiry into the cellular mechanism of heart regeneration. Identifying pathways affecting non-myocytes such as epicardial and endocardial cells, will provide further interesting molecular candidates that modulate cardiomyocyte proliferation, migration or neovascularization. Results obtained from the zebrafish model will complement those from other models and contribute valuable insights for better understanding heart regeneration toward the ultimate goal of treating heart failure.