Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene.
Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibroadipocytes. Cellular origin(s) of fibroadipocytes in AC is unknown.



To identify the cellular origin of adipocytes in AC.



Human and mouse cardiac cells were depleted from myocytes and flow sorted to isolate cells expressing platelet-derived growth factor receptor-α and exclude those expressing other lineage and fibroblast markers (CD32, CD11B, CD45, Lys76, Ly(-6c) and Ly(6c), thymocyte differentiation antigen 1, and discoidin domain receptor 2). The PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) cells were bipotential as the majority expressed collagen 1 α-1, a fibroblast marker, and a subset CCAAT/enhancer-binding protein α, a major adipogenic transcription factor, and therefore, they were referred to as fibroadipocyte progenitors (FAPs). FAPs expressed desmosome proteins, including desmoplakin, predominantly in the adipogenic but not fibrogenic subsets. Conditional heterozygous deletion of Dsp in mice using Pdgfra-Cre deleter led to increased fibroadipogenesis in the heart and mild cardiac dysfunction. Genetic fate mapping tagged 41.4±4.1% of the cardiac adipocytes in the Pdgfra-Cre:Eyfp:Dsp(W/F) mice, indicating an origin from FAPs. FAPs isolated from the Pdgfra-Cre:Eyfp:Dsp(W/F) mouse hearts showed enhanced differentiation to adipocytes. Mechanistically, deletion of Dsp was associated with suppressed canonical Wnt signaling and enhanced adipogenesis. In contrast, activation of the canonical Wnt signaling rescued adipogenesis in a dose-dependent manner.



A subset of cardiac FAPs, identified by the PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) signature, expresses desmosome proteins and differentiates to adipocytes in AC through a Wnt-dependent mechanism. The findings expand the cellular spectrum of AC, commonly recognized as a disease of cardiac myocytes, to include nonmyocyte cells in the heart.
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.). Ali.J.Marian@uth.tmc.edu Raffaella.Lombardi@uth.tmc.edu.
Raffaella
R
Lombardi
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.).
Suet Nee
SN
Chen
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.).
Alessandra
A
Ruggiero
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.).
Priyatansh
P
Gurha
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.).
Grazyna Z
GZ
Czernuszewicz
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.).
James T
JT
Willerson
From the Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Science Center at Houston (R.L., S.N.C., A.R., P.G., G.Z.C., A.J.M.); and Department of Medicine, Texas Heart Institute, Houston (J.T.W.). Ali.J.Marian@uth.tmc.edu Raffaella.Lombardi@uth.tmc.edu.
Ali J
AJ
Marian
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D051180:Desmoplakins
adipocytes; cardiomyopathies; genetics; heart failure; stem cells