Kicking the epicardium up a notch.

The epicardium is a layer of fibrous mesothelium that covers the external surface of the heart. Until recently, the main function of this tissue was thought to be protective and to contribute to production of pericardial fluid. Recently, however, renewed interest in the function of the epicardium has identified important contributions to cardiac development, disease, and regeneration. In the developing embryo, the epicardium derives from the proepicardial organ, a cluster of multipotent progenitor cells located dorsal to the looped heart tube during early stages of embryogenesis.1,2 Some proepicardial cells undergo an epithelial-to-mesenchymal transition (EMT) to generate migratory cells that encase the heart, invade the myocardium, and ultimately give rise to fibroblasts, coronary smooth muscle, and possibly endothelial cells and cardiomyocytes.3–9 The embryonic epicardium provides factors necessary for the normal development and expansion of the myocardium; disruption of critical epicardial signaling pathways leads to thin and poorly functioning myocardium.10–12 These discoveries have raised the question of whether the epicardium might play a role in adult cardiac homeostasis or response to injury by providing cells or growth factors that impact cardiac function. Several recent studies, including a study by Russell et al in this issue of Circulation Research,13 have begun to establish a novel paradigm for the adult epicardium as a tissue able to undergo dynamic activation in response to stress reminiscent of embryonic epicardial EMT. Prior studies in zebrafish have demonstrated generalized activation of the epicardium following amputation of the apex of the heart, which subsequently provides a conducive environment for cardiac regeneration.14,15 Although mammalian hearts do not regenerate as well as those of zebrafish, studies in mice have also demonstrated generalized activation of the epicardium of adult animals after injury and in response to specific factors induced by injury. For example, Bock-Marquette et al showed reactivation of fetal genes and upregulation of nuclear -catenin with evidence for EMT after injury or after administration of the growth factor thymosin 4.16 Interestingly, thymosin 4 is necessary for coronary artery development and may function to enhance neovascularization, perhaps by activating epicardium, after myocardial infarction.17 Russell et al identify a novel population of epicardialassociated cells in the adult mouse heart that is activated and expanded by injury.13 This heterogenous population of cells is defined by evidence of Notch activation (and are therefore named “Notch-activated epicardial-derived cells,” or NECs). These cells resemble multipotent stromal cells (mesenchymal stem cells) by gene expression profiling yet express some cardiac markers in addition to those of the fibroblast lineage. They are c-kit–negative and do not efflux Hoechst dye, and only a subpopulation express sca1, suggesting that they are distinct from previously studied cardiac progenitor populations. NECs become more abundant after myocardial infarction or thoracic aortic banding, although the kinetics of activation and the pattern of cellular localization within the heart are distinct. Injury provokes upregulation of genes promoting fibroblast differentiation and downregulation of musclespecific genes when compared with NECs from uninjured hearts, consistent with the propensity of the mammalian heart to form a fibrotic scar in response to myocardial damage. Scar formation is both beneficial and detrimental. In the short-term, it stabilizes the damaged myocardial wall and prevents rupture. However, in the long-term, scar formation may inhibit endogenous myocardial regeneration, fibrosis may impede diastolic and systolic function, and this process may augment the development of heart failure and lethal ventricular arrhythmias. The extent to which the regenerative capacity of subepicardial progenitors is conserved from zebrafish to mammals remains to be seen. However, broad activation of the epicardium and conditioning of the subepicardial environment in response to injury is at least partially conserved. It is intriguing to speculate that blocking epicardial EMT may affect the fibrotic response to pressure overload, and perhaps a better understanding of the role of epicardial-derived cells in the repair process will provide new therapeutic targets for the modulation of postinfarct remodeling and regeneration. The signaling cascades that result in generalized activation of the entire epicardium, even at sites remote from injury, remain unclear. However, if the same occurs in humans, this phenomenon might help to explain a troublesome complication of myocardial infarction and cardiac surgery. Dressler syndrome, which presents days to weeks after a myocardial infarction or surgical intervention, is associated with inflammation of the pleura and pericardium, chest pain and fever. This phenomenon has been attributed to an immune-mediated response to myocardial injury, but perhaps it reflects an evolutionarily conserved mesothelial activation response contributing to repair. Whether or not epicardially derived cells can give rise to newly regenerated cardiomyocytes is controversial.3,8,9 To determine whether NECs have cardiac differentiation potential, Russell et al transplanted these cells in vivo into The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Cell and Developmental Biology, the Cardiovascular Institute, and the Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia. Correspondence to Jonathan A. Epstein, 1154 BRB II, 421 Curie Ave, Philadelphia, PA 19104. E-mail [email protected] (Circ Res. 2011;108:6-8.) © 2011 American Heart Association, Inc.