Epicardial Lineages and Cardiac Repair

Manvendra Singh,Jonathan Epstein

doi:10.3390/jdb1020141

Abstract

The death of cardiac myocytes resulting from myocardial infarction is a major cause of heart failure worldwide. Effective therapies for regenerating lost cardiac myocytes are lacking. Recently, the epicardium has been implicated as a source of inflammatory cytokines, growth factors and progenitor cells that modulate the response to myocardial injury. During embryonic development, epicardially-derived cells have the potential to differentiate into multiple cardiac lineages, including fibroblasts, vascular smooth muscle and potentially other cell types. In the healthy adult heart, epicardial cells are thought to be generally quiescent. However, injury of the adult heart results in reactivation of a developmental gene program in the epicardium, which leads to increased epicardial cell proliferation and differentiation of epicardium-derived cells (EPDCs) into various cardiac lineages. Recent work suggests that epicardial reactivation after injury is accompanied by, and contributes to, a robust inflammatory response. In this review, we describe the current status of research related to epicardial biology in cardiac development and regeneration, highlighting important recent discoveries and ongoing controversies.

Highlights

The development of the epicardium is conserved through the evolution of vertebrates
Administration of retinoic acid (RA) to heart slices cultured in the absence of the epicardium failed to rescue cardiac myocyte proliferation in these experiments, suggesting that RA does not have a direct mitogenic effect on myocardium [55]. These results suggest that epicardium may modulate myocardial growth by producing a mitogen whose expression is regulated by RA
The epicardium has emerged as a fascinating and dynamic tissue that can contribute to a variety of cardiac lineages in the embryo and in the adult

Summary

Introduction

The development of the epicardium is conserved through the evolution of vertebrates. The epicardial layer of the heart derives from an embryonic anlage, known as the proepicardial organ (PEO), which is a transient structure that arises from the mesothelium of the septum transversum. At ~E9.5 in the mouse, cells from the PEO migrate onto the surface of the heart to form a third heart layer: embryonic epicardium [1±4]. Loss of Dicer, a microRNA-processing enzyme, in the epicardium results in coronary vasculature defects, due to reduced epicardial cell proliferation, differentiation and EMT [9]. Loss of Tbx in the epicardium does not affect epicardial development and function (perhaps due to functional redundancy by other T-box factors), epicardial expression of a transcriptional activator version of Tbx (Tbx18VP16) results in premature smooth muscle differentiation of epicardial cells, due to activated transforming growth factor-beta receptor (TGFßR) and Notch signaling in the embryonic epicardium [19]. Reciprocal paracrine signaling between the epicardium and myocardium regulates coronary vasculature development, as well as cardiomyocyte proliferation and differentiation [8,10,27±29].

Epicardial Lineages

Interaction between Epicardium and Myocardium

Epicardium and Cardiac Regeneration

Findings

Conclusions and Future Perspectives