Origin, Fate, and Function of Epicardium-Derived Cells (EPDCs) in Normal and Abnormal Cardiac Development

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.

Podoplanin deficient mice show a rhoa‐related hypoplasia of the sinus venosus myocardium including the sinoatrial node

“…Another option, is that abnormal epicardial-myocardial interaction plays a role in development of deficient myocardium as is seen in SP3 mutant mouse (Van Loo et al, 2007). We already described the deficient EPDC contribution in the podoplanin mutant (Lie-Venema et al, 2007;Mahtab et al, 2008). Therefore, both the hypoplasia of the atrial septum as well as the dorsal atrial wall observed in the current study, are related to the altered contribution of myocardial and epicardial cells from the PHF.…”

“…Studying the mesenchymal population, podoplanin expression was observed in the proepicardial organ and epicardium Lie-Venema et al, 2007;Mahtab et al, 2008). In the cardiomyocyte population podoplanin staining was seen in major parts of the developing atrioventricular cardiac conduction system, in sinus venosus myocardium including the sinoatrial node, the venous valves, the dorsal mesocardium, the dorsal atrial wall and primary atrial septum.…”

Platelet‐derived growth factor is involved in the differentiation of second heart field‐derived cardiac structures in chicken embryos

“…Myocardium added to the inflow tract (IFT) or venous pole is also derived from the second heart field, and has been referred to as posterior heart field (PHF; Mahtab et al, 2008). The outermost layer of the heart, the epicardium, develops initially as a cauliflower-like mesothelial primordium, the proepicardial organ (PEO), which is located near the sinus venosus (Viragh et al, 1993;Vrancken Peeters et al, 1999;Lie-Venema et al, 2007). In our view, the PEO is part of the PHFderived structures (Mahtab et al, 2008).…”

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

“…In this respect, the more caudal position of the pulmonary and systemic veins in Id2 knockout embryos might represent a failure of correct looping of these hearts, resulting in either a ''primitive'' caudal position of these veins, or malpositioning of the inflow region of the heart dorsal to the ventricular segment, as was also observed in Tbx3 knockout embryos (Mesbah et al, 2008b). Thinning of the ventricular myocardium was described previously in mouse after mutation of podoplanin (Mahtab et al, 2008) and Pdgfr-a and in chick after epicardial ablation (Lie-Venema et al, 2007), and attributed in these models to disturbed epicardial contribution from the PHF.…”