Regulation of Epicardial Cell Fate during Cardiac Development and Disease: An Overview

Abstract

The epicardium is the outermost cell layer in the vertebrate heart that originates during development from mesothelial precursors located in the proepicardium and septum transversum. The epicardial layer plays a key role during cardiogenesis since a subset of epicardial-derived cells (EPDCs) undergo an epithelial-mesenchymal transition (EMT); migrate into the myocardium; and differentiate into distinct cell types, such as coronary vascular smooth muscle cells, cardiac fibroblasts, endothelial cells, and presumably a subpopulation of cardiomyocytes, thus contributing to complete heart formation. Furthermore, the epicardium is a source of paracrine factors that support cardiac growth at the last stages of cardiogenesis. Although several lineage trace studies have provided some evidence about epicardial cell fate determination, the molecular mechanisms underlying epicardial cell heterogeneity remain not fully understood. Interestingly, seminal works during the last decade have pointed out that the adult epicardium is reactivated after heart damage, re-expressing some embryonic genes and contributing to cardiac remodeling. Therefore, the epicardium has been proposed as a potential target in the treatment of cardiovascular disease. In this review, we summarize the previous knowledge regarding the regulation of epicardial cell contribution during development and the control of epicardial reactivation in cardiac repair after damage.

Keywords: cardiac damage; cardiac development; epicardium.

Figure 1

Epicardial development across species. In chick and zebrafish embryos, proepicardial cells migrate to the myocardial surface by formation of extracellular matrix (ECM) bridges (orange arrows). In mammals, the proepicardial cells migrate through the formation of free-floating cell aggregates or by direct contact with the myocardial surface (blue arrows).

Figure 2

Cellular and molecular interactions during epicardial development and after injury. (A) A subset of epicardial cells, called epicardium-derived progenitor cells (EPDCs), undergo epithelial-to-mesenchymal transition (EMT); delaminate and migrate into the subepicardium; and differentiate into different cell types: fibroblasts, adipocytes, endothelial cells, vascular smooth muscle cells, and potentially cardiomyocytes. Many factors (red) have been described to be involved in driving epicardial EMT and EPDC migration and differentiation. (B) After cardiac injury, reactivated epicardial cells express genetic embryonic programs, undergo EMT, and migrate into the underlying tissue, where they differentiate into adipocytes or fibroblasts. Furthermore, the epicardium reactivation is accompanied by the secretion of paracrine factors and by an adaptive immune response.