More than Just a Simple Cardiac Envelope; Cellular Contributions of the Epicardium

Abstract

The adult pumping heart is formed by distinct tissue layers. From inside to outside, the heart is composed by an internal endothelial layer, dubbed the endocardium, a thick myocardial component which supports the pumping capacity of the heart and exteriorly covered by a thin mesothelial layer named the epicardium. Cardiac insults such as coronary artery obstruction lead to ischemia and thus to an irreversible damage of the myocardial layer, provoking in many cases heart failure and death. Thus, searching for new pathways to regenerate the myocardium is an urgent biomedical need. Interestingly, the capacity of heart regeneration is present in other species, ranging from fishes to neonatal mammals. In this context, several lines of evidences demonstrated a key regulatory role for the epicardial layer. In this manuscript, we provide a state-of-the-art review on the developmental process leading to the formation of the epicardium, the distinct pathways controlling epicardial precursor cell specification and determination and current evidences on the regenerative potential of the epicardium to heal the injured heart.

Actomyosin dynamics, Bmp and Notch signaling pathways drive apical extrusion of proepicardial cells

“…Moreover, loss of function of Notch signaling alters epicardium formation and Notch signaling regulates smooth muscle differentiation of epicardium-derived cells 53 . To study the link between Notch and Bmp2 signaling pathways during PE formation in the zebrafish, we used the transgenic line UAS:NICD-myc KCA 4 54 to overexpress the intracellular active domain of the Notch receptor (NICD) under a HS-inducible promoter hsp70:Gal4 KCA3 . When we performed HS in this line at 48 hpf, PE formation was unaltered at 60 hpf when compared with non-transgenic zebrafish (8 ± 4 cells vs 8 ± 3 cells, respectively) (Fig.…”

“…The epicardium is also an important cell source during embryogenesis. Epicardial-derived progenitor cells (EPDCs) differentiate into cardiac fibroblasts as well as other cell types including adipocytes 3 , mesenchymal stem cells, and smooth muscle or endothelial cells of the coronary vessels, and contribute to the formation of the annulus fibrosus and the valves 4, 5 . After heart injury, EPDCs are involved in several aspects of tissue repair and regeneration, contributing to cardiac fibrosis, controlling the inflammatory response, promoting neoangiogenesis and cardiomyocyte proliferation 6 .…”

Proepicardium: Current Understanding of its Structure, Induction, and Fate

“…There are disputable data claiming that EPDCs may differentiate into coronary endothelial cells. This seems to be true for some of the proepicardial cell population (Duenas et al, 2017). The GATA4 transcription factor was detected in the cardiac and extracardiac tissues of the mouse at ED 9.5 (Arceci et al, 1993;Kelley et al, 1993;Watt et al, 2004).…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…A better understanding of coronary vascular development is key to developing better therapies for heart disease. Great efforts have been recently made to elucidate the complex program of the formation coronary vessels, which has been discussed in several excellent reviews (Duenas, Aranega, & Franco, 2017;Sharma, Chang, et al, 2017). Briefly, the development of coronary circulation begins with the establishment of a primary endothelial plexus network which is followed by vascular remodeling, arterial-venous specification and the addition of perivascular cells.…”