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  • It is now established that in all vertebrates studied

    2018-10-20

    It is now established that, in all vertebrates studied, Wnt-C59 Supplier from the PEO encapsulate the looping heart at mid-gestation, forming the critical outer layer. The epicardium then enters a complex ‘dialogue’ with the underlying myocardium; secretes trophic factors essential for myocardial maturation, and directly contributes precursors of numerous cardiac cell types. The sequence and mechanisms of this complex interplay are a major research focus, whilst the relative contributions of epicardium-derived cells (EPDCs) to cardiac lineages remain a source of debate. The relevance of understanding epicardial potential in development is paramount given its response to injury. Post-development, embryonic epicardial gene programmes are shut down, at least in mammals, and in the healthy adult heart, the epicardium is said to become quiescent. Following heart injury, however, such ‘quiescence’ is rapidly lost as epicardial cells revert to an embryonic-like phenotype, proliferating at the site of injury and secreting factors to modulate wound healing. In adult mammals, this response is characterised by mass fibrosis and scar formation, which, whilst necessary to prevent exsanguination of the compromised ventricle and retain contractile force, ultimately leads to pathological remodelling and heart failure. Conversely, organ-wide epicardial activation in the zebrafish heart in response to injury is central to the regenerative capacity of this species (Kikuchi et al., 2011; Lepilina et al., 2006). It has long been known that the mammalian heart is very limited in its regenerative capacity. Shortly after birth, a majority of cardiomyocytes (CMs) exit the cell cycle, and whilst there is evidence of limited turnover (of between 0.5 and 1% per year in adult humans during normal homeostasis (Bergmann et al., 2009)), muscle regeneration is insufficient to restore the billions of CMs lost post-infarction. That is, unless the infarction occurs during the first few days of life. Recently, Porrello and colleagues demonstrated the remarkable regenerative capacity of the neonatal mouse heart. Following amputation of 15–20% of the apex (Porrello et al., 2011) or ischemia induced by chronic ligation of the lateral anterior descending coronary artery (LAD) (Porrello et al., 2013; Haubner et al., 2012), the neonate (one day old) was shown to regenerate lost myocardium in a timescale that exceeds the regenerative capacity of zebrafish. However, this capacity was lost within the first week of life, such that if the same injury was sustained on or after postnatal day (P) 7, default scar formation and adult-like wound healing was observed. This first demonstration of effective mammalian heart regeneration was again associated with organ-wide epicardial activation, and was lost coincident with the loss of epicardial potential (Chen et al., 2002).
    The epicardium in heart development At around Embryonic day (E) 9.75 in the mouse, Hamburger Hamilton (HH) stage 18 in the chick, and 72h post fertilisation (hpf) in the zebrafish; the mature PEO migrates to the myocardial surface to encapsulate the heart. After forming a uniform epithelium (at around E11 or equivalent) a proportion of epicardial cells undergo epithelial-to-mesenchymal transition (EMT) and populate the subepicardial space. EPDCs then migrate into the underlying myocardium and give rise to numerous cardiac lineages.
    The ‘quiescent’ epicardium Following development, the epicardium becomes relatively dormant. Chen and colleagues described the loss of epicardial potential by P4 in the mouse; simultaneous with a loss of myocardial responsiveness to epicardial paracrine secretions (Chen et al., 2002). Early embryonic marker genes, including Raldh2, were switched off, with low levels persisting only in epicardium surrounding the atria and atrioventricular sulcus (AVS) in the mouse (van Wijk et al., 2012; Zhou et al., 2011). The role of the epicardium in adult mammalian heart homeostasis is not well characterised, but in the adult zebrafish the epicardium is suggested to regularly contribute to myocardial homeostasis via an FGF dependent dialogue with CMs throughout life (Wills et al., 2008), and may underpin continual CM turnover in the zebrafish heart.