Cell Specific Reactivation of Epicardium at the Origin of Fibro-Fatty Remodeling of the Atrial Myocardium

Epicardium, the mesothelium covering the heart, is composed of multipotent cells and is reactivated following myocardial injury in adults. Herein, we provide evidence for activation of atrial epicardium in aged patients with diseased atria and in murine models of atrial remodeling. Epicardial activation contributed to fibro-fatty infiltration of sub-epicardium that contained a number of cells co-expressing markers of epicardial progenitors and fibroblasts. Indeed, using genetic lineage tracing of adult epicardium, we demonstrate the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of adult epicardial-derived cells (aEPDCs) expressing PDGFRalpha;niched in the sub-epicardium, were isolated and differentiated into myofibroblast in the presence of angiotensin-II. Furthermore, single cell RNA-seq analysis identified several clusters of aEPDCs and revealed transition from adipogenic to fibrogenic cells. In conclusion, a subset of aEPDCs, pre-programmed towards a specific cell fate, contributes to fibro-fatty infiltration of sub-epicardium of diseased atria.