Abstract
During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation.Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae.With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.
Highlights
In vertebrate development, heart morphogenesis is initiated by the fusion of two cardiogenic primordia of the splanchnopleuric mesoderm[1,2]
Whereas little is known about the factors that induce initial proepicardial organ (PEO) formation, the differentiation of the PEO into a migrating mesothelium distinct from the cardiac cells of the sinus venosus wall is known to be regulated by bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling[16,33]
It is relatively thin at the atrial and ventricular myocardium, whereas it is thick in the atrioventricular sulcus where abundant epithelialmesenchymal transformation (EMT) will provide for all the epicardium-derived cells (EPDCs) needed for coronary formation[45]
Summary
Heart morphogenesis is initiated by the fusion of two cardiogenic primordia of the splanchnopleuric mesoderm[1,2]. Endocardial cushions are formed at the future atrioventricular junction and in the outflow tract At this point in development, two extracardiac sources start to deliver cells in and onto the heart tube. Migrating cells originating from the cardiac neural crest invade the heart via the aortic arches[3,4] They contribute to the formation of the aorticopulmonary septum and outflow tract endocardial cushions[5,6,7]. Cardiac neural crest cells (CNCs) enter the inflow portion of the heart via remnants of the dorsal mesocardium They migrate into the dorsal mesenchymal protrusion forming the vestibular spine, from where they contribute to the base of the atrial septum and the condensed mesenchyme that is forming the membranous part of the ventricular septum[8,9,10]. These so-called epicardium-derived cells (EPDCs) have both constructive and instructive roles in heart morphogenesis, which will both be discussed in this review
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