br The reactive epicardium in the non regenerative injury

The ‘reactive’ epicardium in the non-regenerative injury response Following myocardial infarction (MI) in adult mammals, billions of CMs are lost and replaced by proliferation and activation of fibroblasts which deposit ECM (most notably collagen) which results in scar formation. Whilst required as an immediate and early response to prevent organ rupture, the resulting loss in contractile function results in changes to ventricular geometry (enlargement and dilation) which in turn causes haemodynamic uncoupling and progressive deterioration of pump function (Jugdutt, 2003; Jessup and Brozena, 2003). For over a century, animal models of heart injury have facilitated understanding of the pathophysiological consequences of MI and heart failure. Traditionally, this has been induced by ligation of the LAD to induce temporary or permanent occlusion of blood flow to the left ventricle (with or without reperfusion, respectively) and consequent MI facilitating studies on cardiovascular wound healing and repair.
The ‘reactive’ epicardium in heart regeneration In hmg-coa reductase inhibitors to the insufficient endogenous repair mechanisms of the adult mammalian heart, many lower vertebrates, and recently the neonatal mouse, have been shown to retain remarkable regenerative capacities following substantial cardiac injury. Early seminal work revealed the first demonstrations of vertebrate heart regeneration in the newt: following amputation of 10% of the ventricle, the newt heart showed signs of regeneration within 30days (Oberpriller and Oberpriller, 1974). More recently, regenerative responses to heart injury have been extrapolated to the adult zebrafish and neonatal mouse (Porrello et al., 2011, 2013; Haubner et al., 2012; Poss et al., 2002; Xin et al., 2013a; Gonzalez-Rosa and Mercader, 2012). The amenability of these species to both forward and reverse genetics has facilitated investigation into the underlying cellular and molecular basis for heart regeneration across evolution. There are, however, important distinctions between the animal model organisms, as outlined in Table 1, which all likely contribute to the responses to cardiac injury.
Concluding remarks Heart regeneration in lower vertebrates and neonatal mice is characterised by two conserved events: organ-wide epicardial activation and proliferation of pre-existing CMs. These events parallel the epicardial–myocardial signalling that is crucial for heart formation during embryonic development, as outlined in Fig. 1. Organ-wide epicardial activation is also a hallmark of the injury response of adult mammals; but in this setting, cardiac fibroblasts represent the proliferative population, and fibrotic wound healing ensues. Myogenic cues are thus an important factor for heart regeneration. It is widely assumed that the transient and persistent mononuclear status of CMs in zebrafish and neonatal mouse hearts, respectively, underpins their ability to proliferate; and thereby the capacity of these animals to regenerate following cardiac injury (Xin et al., 2013b; Muralidhar et al., 2013). Indeed, recent studies demonstrated that manipulation of factors which influence cell-cycle arrest hold potential in extending the regenerative capacity of the neonatal mouse heart beyond the first week of life (Porrello et al., 2013; Xin et al., 2013a; Mahmoud et al., 2013). Here we highlight epicardial signals as critical myogenic cues instructing myocardial formation and growth during both heart development and regeneration. In particular, epicardial–RA signalling is a potent mitogen for CMs; the loss of which impedes myogenesis. Following MI in the adult mouse, epicardial RA synthesis is reactivated, and activation of RA responsive genes is observed in both CMs and cardiac fibroblasts; though significantly more so in the latter, which is associated with fibrosis. The divergent RA influence in these settings likely reflects inherent differences in the CMs of the respective model systems. The ability of mammalian CMs to respond to epicardial–RA signalling is reportedly lost in the first week of life in mice, whilst the proliferative capacity of zebrafish CMs is retained throughout adulthood. The extent and source of RA signalling in these different animal models may be significant, given the endocardial supplement observed in the lower vertebrate injury response. The coincident timing of a loss of epicardial RA with the ‘switch’ in mammalian regenerative to non-regenerative injury response, however, is intriguing. Although a role for RA signalling during the ‘regenerative window’ in the neonatal mouse is unexplored, it is tempting to speculate that restoration of RA–epicardial–myocardial signalling may positively influence CM proliferation and thereby extend regeneration of the post-natal mouse heart beyond the first week of life. Similarly, FGFs, as potential downstream RA targets with mitogenic roles in development and both zebrafish heart homeostasis and regeneration, may also offer targets for promoting mammalian heart regeneration. Improved understanding of the relative contributions of epicardial–myocardial FGF signalling pathways across species is required to appreciate any potential therapeutic relevance in the regenerative setting.