Cardiac Fibro-Adipocyte Progenitors Express Desmosome Proteins and Preferentially Differentiate to Adipocytes Upon Deletion of the Desmoplakin Gene
Rationale: Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibro-adipocytes. Cellular origin(s) of fibro-adipocytes in AC is unknown.
Objective: To identify the cellular origin of adipocytes in AC.
Methods and Results: Human and mouse cardiac cells were depleted from myocytes and flow sorted to isolate cells expressing platelet-derived growth factor receptor A (PDGFRA) and exclude those expressing other lineage and fibroblast markers (CD32, CD11B, CD45, Lys76, Ly-6c and Ly6c, THY1, and DDR2). The PDGFRApos:Linneg:THY1neg:DDR2neg cells were bipotential, as the majority expressed COL1A1, a fibroblast marker, and a subset CEBPA, a major adipogenic transcription factor, and therefore, were referred to as fibro-adipogenic progenitors (FAPs). FAPs expressed desmosome proteins including desmoplakin (DSP), predominantly in the adipogenic but not fibrogenic subsets. Conditional heterozygous deletion of Dsp in mouse using Pdgfra-Cre deleter led to increased fibro-adipogenesis in the heart and mild cardiac dysfunction. Genetic fate mapping tagged 41.4±4.1% of the cardiac adipocytes in the Pdgfra-Cre:Eyfp:DspW/F mice, indicating an origin from FAPs. FAPs isolated from the Pdgfra-Cre:Eyfp:DspW/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.
Conclusions: A subset of cardiac FAPs, identified by the PDGFRApos:Linneg:THY1neg:DDR2neg signature, expresses desmosome proteins and differentiates to adipocyte 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 non-myocyte cells in the heart.
- Received December 8, 2015.
- Revision received April 11, 2016.
- Accepted April 27, 2016.