Understanding Epicardial Cell Heterogeneity during Cardiogenesis and Heart Regeneration

Abstract

The outermost layer of the heart, the epicardium, is an essential cell population that contributes, through epithelial-to-mesenchymal transition (EMT), to the formation of different cell types and provides paracrine signals to the developing heart. Despite its quiescent state during adulthood, the adult epicardium reactivates and recapitulates many aspects of embryonic cardiogenesis in response to cardiac injury, thereby supporting cardiac tissue remodeling. Thus, the epicardium has been considered a crucial source of cell progenitors that offers an important contribution to cardiac development and injured hearts. Although several studies have provided evidence regarding cell fate determination in the epicardium, to date, it is unclear whether epicardium-derived cells (EPDCs) come from specific, and predetermined, epicardial cell subpopulations or if they are derived from a common progenitor. In recent years, different approaches have been used to study cell heterogeneity within the epicardial layer using different experimental models. However, the data generated are still insufficient with respect to revealing the complexity of this epithelial layer. In this review, we summarize the previous works documenting the cellular composition, molecular signatures, and diversity within the developing and adult epicardium.

Keywords: cardiac development; cardiac repair; epicardium; heterogeneity.

Figure 1

Cell heterogeneity of the epicardium during heart development. At E7.75–8.0, cardiac progenitor cells extend towards the midline to form the cardiac crescent or first heart field (FHF, shown in red) in the caudal direction with respect to the headfolds. In the rostral direction with respect to the FHF, there is a population of progenitor cells, constituting the juxta-cardiac field (JCF, shown in light blue). The second heart field (SHF) is composed of two subdomains: anterior (shown in dark green) and posterior (illustrated in light green). At E8.5–9.5, cardiac crescent fusion and posterior looping at the midline form the early cardiac tube. PE is situated in the venous inflow tract in the developing primitive heart. At around E10–11.5, clusters of PE cells begin to proliferate and spread, covering the heart tube with an epithelial layer, the epicardium. New experimental data have proposed (question marks) that EPDCs with specific cell fates (fibroblasts or muscle cells) might originate from different epicardial cell subpopulations.