P1232A subpopulation of epicardium-derived cells are preprogrammed towards fibroblast differentiation in the atrial myocardium

Abstract

Abstract Context and objectives Fibro-fatty infiltrations of the sub-epicardium is an important component of the atrial cardiomyopathy that paves the way of atrial fibrillation (AF). We previously reported that epicardium-derived cells (EPDCs) can be a source of adipocytes contributing to fat depot. Here, we examined if EPDCs can contribute also to the fibrotic remodeling of atrial subepicardium. Methods Surgical samples of human right atria were used for histological study and to harvest EPDCs. Clinical and histological data were analyzed using generalized linear models. A model atrial remodeling associated with ischemic heart failure was created in rats and in a genetic lineage tracing WT1CreERT2+/−/Rosa-tdT+/− mice to follow epicardial progenitor fate. Primary cell culture models were used to study EPDC differentiation. Flow cytometry assays and single cell sequencing were used to characterize subpopulations of EPDCs. Results In human atria, epicardium could be a thin cell monolayer or be thick in continuity with dense fibro-fatty infiltrates. The latter aspect predominated in old patient (>70 year) with valve mitral diseases or in AF, clinical conditions associated with an atrial remodeling. This was further established in rat and mouse experimental model of atrial remodeling characterized by a thickening of the epicardium observed one week following the onset of the cardiopathy and, then, followed by a dense fibrotic remodeling of the subepicardium. Cells co-expressing markers of epicardial progenitors and fibroblasts were detected in the subepicardium of diseased atria both in human and murine models. Moreover, a number of myo/fibroblasts from WT1CreERT2+/−/Rosa-tdT+/− mice were detected in diseased atria attesting of their epicardial origin. Distinct EPDC clusters were detected from cells harvested from epicardium whereas only PDGFRa-positive cells could differentiated into fibroblasts. Angiotensin-II induced the differentiation of only PDGFRa-positive cells into fibroblasts. Conclusions Activation of the epicardium is an early event during atrial remodeling that results in the triggering of differentiation of a subpopulation of epicardial progenitors into fibroblasts. Angiotensin-II is part of the signaling switch than regulate the fate of EPDC between fibroblastic or adipogenic lineage. Hence, epicardium by regulating the balance between adipose expansion and fibrosis accumulation appears as an important determinant of the atrial cardiomyopathy. Acknowledgement/Funding ANR-10-IAHU-05