Epicardium-derived cells (EPDCs) in development, cardiac disease and repair of ischemia

Abstract

Reactivation of endogenous epicardium after ischemia The proepicardial-derived epicardium covers the myocardium and after a process of epithelial-mesenchymal transition (EMT) forms epicardium-derived cells (EPDCs). These cells migrate into the myocardium and show an essential role in the induction of the ventricular compact myocardium and the differentiation of the Purkinje fibres. EPDCs are furthermore the source of the interstitial fibroblast, the coronary smooth muscle cell and the adventitial fibroblast. The possible differentiation into cardiomyocytes, endothelial cells and the recently described telocyte and other cells in the cardiac stem cell niche needs further investigation. Surgically or genetically disturbed epicardial and EPDC differentiation leads to a spectrum of abnormalities varying from thin undifferentiated myocardium, which can be embryonic lethal, to a diminished coronary vascular bed with even absent main coronary arteries. The embryonic potential of EPDCs has been translated to both structural and functional congenital malformations and adult cardiac disease, like development of Ebstein's malformation, arrhythmia and cardiomyopathies. Furthermore, the use of adult EPDCs as a stem cell source has been explored, showing in an animal model of myocardial ischemia the recapitulation of the embryonic program with improved function, angiogenesis and less adverse remodeling. Combining EPDCs and adult cardiomyocyte progenitor cells synergistically improved these results. The contribution of injected EPDCs was instructive rather than constructive. The finding of reactivation of the endogenous epicardium in ischemia with re-expression of developmental genes and renewed EMT marks the onset of a novel therapeutic focus.

Fig 1

(a) Schematic representation of the first and second heart field contribution to the developing heart. The venous pole (posterior heart field) is essential as source of EPDCs and CMPCs, a differentiation in a myocardial and epicardial lineage from the progenitor population is guided by the balance of bone morphogenetic protein (BMP) and fibroblastic growth factor 2 (Fgf2) [27]. (b) Expression of WT1 in the surface epicardium (b1) and intramyocardially (b2) in a control adult mouse heart is very limited (arrows). Two days after MI, with injection of medium, this is not substantially altered (c1,2) except for the cases with injection of EPDCs (c3,4), where both the surface epicardium and the interstitial fibroblasts show marked WT1 expression. At day 4 after MI this phenomenon is also present in the medium injected heart (d1,2) and maintained in the heart after EPDC transplantation (d3,4). Injection of the lentiviral Katushka construct into the epicardial cavity showed, after 4 days survival, staining of the squamous surface epicardium in the control heart (e, arrows). After MI the surface epicardium becomes cuboid (f, arrows) indicative of activation and cells can be traced intramyocardially (g, arrows) after EMT, which is supported by double staining of Katushka and WT1 (h). Scale bars b1–d4:30 μm, e–h:50 μm.