Common Epicardial Origin of Coronary Vascular Smooth Muscle, Perivascular Fibroblasts, and Intermyocardial Fibroblasts in the Avian Heart

Abstract

Previous studies have shown that during avian heart development, epicardial and coronary vascular smooth muscle precursors are derived from the proepicardium, a derivative of the developing liver. This finding led to a model of coronary vascular development in which epicardial cells migrate over the postlooped heart, followed by migration of committed endothelial and smooth muscle precursors from the proepicardium through the subepicardial matrix where the coronary arteries develop. Here we show that epicardial cells undergo epithelial-mesenchymal transformation to become coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts. We began by establishing primary cultures of quail epicardial cells that retain morphologic and antigenic identity to epicardial cells in vivo. Quail epicardial monolayers stimulated with serum or vascular growth factors produced invasive mesenchyme in collagen gels. Chick epicardial cells labeled in ovo with DiI invaded the subepicardial extracellular matrix, demonstrating that mesenchymal transformation of epicardium occurs in vivo. To determine the fates of epicardially derived mesenchymal cells, quail epicardial cells labeled in vitro with LacZ were grafted into the pericardial space of E2 chicks. These cells attached to the heart, formed a chimeric epicardium, invaded the subepicardial matrix and myocardial wall, and became coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts, demonstrating the common epicardial origin of these cell types. A general model of coronary vascular development should now include epicardial-mesenchymal transformation and direct participation of mesenchyme derived from the epicardium in coronary morphogenesis.

The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells

“…Almost 20 years later, we showed that this process also takes place in the epicardium where it results in the formation of subepicardial mesenchyme (Pérez-Pomares et al, 1997). The mesenchymal cells that migrate into the subepicardial space and that are derived from the proepicardially derived primitive epicardium (Pérez-Pomares et al, 1997, 1998a, 1998bDettman et al, 1998) are generally referred to as EPDCs (see above).…”

“…The space that is sandwiched between the myocardium and epicardium is known as the subepicardium or subepicardial space. Within the subepicardial space, subepicardial mesenchymal cells can be found that are derived from the epicardium as a result of epicardial EMT (Pérez-Pomares et al, 1997, 1998aDettman et al, 1998;reviewed in Mä nner et al, 2001). These cells are therefore generally referred to as EPDCs (Gittenberger-de Groot et al, 1998).…”

“…During and after the formation of the epicardial sheet, a subset of epicardial cells detach from their epithelial context ( Fig. 1D) and generate in the subepicardium a population of epicardially derived cells (EPDCs) through an epicardial EMT (Muñ oz-Chá puli et al, 1996;Pérez-Pomares et al, 1997, 1998aDettman et al, 1998;Gittenberger-de Groot et al, 1998). The epicardial EMT is observed at the AV junction, in the ventricular epicardium, and in the epicardium at the junction between the ventricles and the OFT, but not in the atrial epicardium.…”

The Development of the Epicardium in the Sturgeon Acipenser naccarii

“…A feature common to all the species studied is that, following myocardial covering, part of the epicardial cells colonize the space between the epicardium and the myocardium and transform into mesenchyme (Icardo et al, 1990). At subsequent developmental stages, epicardium-derived cells invade the myocardium giving rise to coronary endothelial and smooth muscle cells, cardiac fibroblasts, and blood progenitors (Mikawa and Gourdie, 1996;Pérez-Pomares et al, 1998, 2002Gittenberger-de Groot et al, 1998;Dettman et al, 1998;Männer, 1999;Vrancken Peeters et al, 1999;Pérez-Pomares et al, 2003) (reviewed in Muñ oz-Chápuli et al, 2002;Wessels and Pérez-Pomares, 2004). Epicardium-derived cells also contribute to valve development and to the formation of the fibrous heart skeleton (Gittenbergerde Groot et al, 1998;Lie-Venema et al, 2008).…”

Vasculogenesis of the embryonic heart: Origin of blood island‐like structures

“…Some cells of the epicardial mesothelium possess the ability to migrate to the subepicardial space undergoing epicardial-mesenchymal transformation. These mesenchymal cells are considered to be a source of smooth muscle cells that make up the tunica media of coronary vasculature and interstitial fibroblasts as well as fibroblasts of the adventitia (Mikawa and Gourdie, 1996;Dettman et al, 1998;Gittenberger-de Groot et al, 1998;Vrancken Peeters et al, 1999;Wada et al, 2003). Subepicardial space, particularly at the atrioventricular and interventricular sulcuses, is filled with blood cells, angioblasts, mesenchymal cells, and extracellular matrix material (Virá gh et al, 1993;Ká lmá n et al, 1995).…”