Abstract 20201: Fibro-Adipocyte Progenitors are a Cell Source of Adipocytes in Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is clinically characterized by arrhythmias, heart failure and sudden death and pathologically by replacement of cardiomyocytes by fibro-adipocytes. Mutations in desmosome genes are the main causes of AC. Desmosome proteins are known to be expressed only in cardiac myocytes. Cardiac progenitor cells (CPCs) expressing mutant desmosome proteins could differentiate to adipocytes. However, genetic fate-mapping identify CPCs as the source of a fraction of adipocytes in AC. We posit that cardiac cells other than CPCs express desmosome proteins and differentiate to adipocytes in AC. We systematically determined expression of the desmosome proteins in different cardiac cells. Cardiac fibro-adipocyte progenitors (FAPs), marked by expression of platelet-derived growth factor receptor-α (PDGFRA), expressed mRNAs and proteins of major desmosome genes. FAPs isolated from the heart of Nkx2.5Cre:Dsp W/F mice, an established model of AC, showed enhanced adipogenesis associated with suppression of canonical Wnt signaling (reduced Ccnd1, Ctgf and cMyc mRNA levels by 10-, 5- and 3-fold, respectively, N=5, all p<0.001). To determine whether FAPs are a source of adipocytes in AC, we generated lineage tracer mice, utilizing the Pdgfra-Cre deleter, and conditionally deleted one copy of desmoplakin ( Dsp ) while expressing enhanced yellow fluorescence protein (EYFP) in the FAPs. Recombination efficiency (% of PDGFRA+ cells expressing EYFP) was ~75%. Six to 12 months old lineage tracer mice ( Pdgfra-Cre:Dsp W/F ) showed mild cardiac dysfunction (fractional shortening: 57±9%, N=14 vs. 66±7%, N=10 in controls, p< 0.005) and increased adipocytes in the heart (14±9, N=5 vs. 1±1, N=3 in controls, p=0.03). Co-expression of EYFP and C/EBPA adipogenic marker was detected in 54% of adipocytes in the lineage tracer mice, indicating an origin from FAPs. Dsp +/- FAPs showed enhanced differentiation to adipocytes as compared to control FAPs. The Hippo, canonical Wnt and NOTCH1 signaling pathways in mediating differentiation of Dsp +/- FAPs to adipocytes are being delineated. The findings show cardiac FAPs express desmosome proteins and when haplo-insufficient for Dsp differentiate to adipocytes. Thus, FAPs are a source of adipocytes in AC.