The ontogeny of cardiac regeneration.

The regenerative capacity of adult human hearts after infarction seems vestigial at best, perhaps because of the poor proliferative capacity of terminally differentiated cardiomyocytes and desecration of the local environment that would otherwise be conducive of stem cellmediated repair or loss of stem cells, or both. In a recent edition of the journal Science, Porello et al set a new benchmark in this field by showing that the hearts of neonatal mice have, in contrast, an impressive regenerative capacity after surgical resection, albeit one that is lost almost immediately as cardiomyocytes exit the cell cycle and mature. In a technical tour de force, Porello et al report that day 1 neonatal mice subjected to resection of the apex of the left ventricle (amounting to 15% of the ventricular myocardium) not only survive but also show complete regeneration of the myocardium and restoration of cardiac function. Furthermore, they provide evidence that the predominant mechanism involved is not differentiation of stem cells, but transient dedifferentiation and proliferation of cardiomyocytes in both the border and remote zones of the heart. In contrast, resection of a lesser amount of apical myocardium in day 7 neonates, at a time after terminal differentiation of cardiomyocytes has already taken place, resulted in markedly increased mortality and failure of myocardial regeneration, with wound repair by scar formation only. It has long been known that in adult mammals, the heart is one of the least regenerative organs in the body. As a result, repair after massive tissue injury, as occurs with myocardial infarction, is limited to replacement of the myocardium by dense collagenous scar tissue. This impairs contractile function, resulting in adverse remodelling and, in severe cases, ventricular dilation, heart failure, and death. To explore if intracardiac grafting of cardiomyocytes might be useful to promote myocardial repair, some 17 years ago, Field and colleagues implanted transgenic cardiomyocytes from embryonic day-15 mice, which harboured a fusion gene construct of the -cardiac myosin heavy chain with a -galactosidase reporter, into the hearts of adult syngeneic hosts. In this elegant proof-of-principle study, they showed that these fetal cells, when delivered directly into the myocardium, engrafted; displayed prolonged survival; formed connections with the host myocardium via intercalated discs; and expressed the transgene. Such plasticity of growth, albeit in the context of transplantation of cells into the myocardium of a host animal, is perhaps not surprising given the continued hyperplastic growth of the myocardium during development—plasticity that can fully compensate for loss of up to 50% of cardiomyocytes during the embryonic/fetal period. The replicative competence of cardiomyocytes in the prenatal period in mammals is in stark contrast to their terminal differentiation that commences shortly after birth, as observed in detailed analyses of rat and mouse hearts by Gerdes and coworkers and Field and colleagues. They showed rapid conversion of cardiomyocytes from hyperplastic to hypertrophic growth in the perinatal period, with cessation of cell division after 4 days of age. This was coincident with the onset of binucleation (in rodents) and polyploidy, resulting from a period of continued DNA synthesis in the absence of cytokinesis. Indeed, the replicative ability of mammalian terminally differentiated cardiomyocytes in the injury setting, such as during myocardial infarction, seems trivially small. This terminal state is not observed, however, in certain nonmammalian species, including teleost fish, like Zebrafish, and urodeles, such as newts, which show a high basal level of cardiomyocyte division and sustained cardiomyocyte regeneration, even in adult life, in response to injury. Indeed, complete repair of the myocardium resulting from a stem cell-independent mechanism, involving cell cycle reentry and proliferation of cardiomyocytes, has been demonstrated in Zebrafish after apical resection of at least 20% of the left ventricle or after cryoinjury. Although the findings of Porello et al confirm the known plasticity of embryonic/fetal cardiomyocytes and their terminal differentiation perinatally, the study is nonetheless of importance, both clinically in terms of enhancing myocardial repair and preserving cardiac contractile function after injury, and mechanistically in terms of delineating the molecular pathways underlying myocardial wound healing. From a clinical point of view, it will be relevant to determine if complete repair of the myocardium in the day-1 neonates is possible not only after a relatively atraumatic injury such as apical resection, but also after an injury resulting in a hostile inflammatory environment, as occurs after myocardial infarction. In this regard, it is of interest that in Zebrafish, myocardial repair after cryoinjury, which incites vigorous inflammation, involves marked scar formation, which is nonetheless replaced by regenerated myocardium, albeit after a protracted period, compared with regeneration in the surgical resection model, The opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar and Ali J. Marian. From the Victor Chang Cardiac Research Institute, Developmental Biology Division, Darlinghurst, NS, Australia. Correspondence to Richard P. Harvey, Victor Chang Cardiac Research Institute, Developmental Biology Division, Darlinghurst, NS, Australia. (Circ Res. 2011;108:1304-1305.) © 2011 American Heart Association, Inc.