Cardiac Mesenchymal Stem Cells Promote Fibrosis and Remodeling in Heart Failure

• Resident cardiac mesenchymal stem cells (cMSCs) comprise a distinct mesenchymal population that is temporally expanded and exhibit pro-fibrotic and pro-inflammatory features in failing hearts. • cMSCs in failing hearts undergo a phenotypic switch characterized by enhanced pro-inflammatory and pro-fibrotic responses. • Pro-inflammatory macrophages promote a myofibroblast differentiation fate of cMSCs from failing hearts, in part mediated by platelet-derived growth factor (PDGF)/PDGF receptor β activation. • Pharmacologic PDGF receptor inhibition in a mouse model of myocardial infarction alleviated long-term cardiac remodeling, inflammation, hypertrophy, and fibrosis and increased myocardial capillary density. • Inhibiting the pathologic cMSC phenotype, or restoring a normal cMSC phenotype, may combat the progression of cardiac fibrosis and failure after myocardial infarction. Heart failure (HF) is characterized by progressive fibrosis. Both fibroblasts and mesenchymal stem cells (MSCs) can differentiate into pro-fibrotic myofibroblasts. MSCs secrete and express platelet-derived growth factor (PDGF) and its receptors. We hypothesized that PDGF signaling in cardiac MSCs (cMSCs) promotes their myofibroblast differentiation and aggravates post–myocardial infarction left ventricular remodeling and fibrosis. We show that cMSCs from failing hearts post–myocardial infarction exhibit an altered phenotype. Inhibition of PDGF signaling in vitro inhibited cMSC–myofibroblast differentiation, whereas in vivo inhibition during established ischemic HF alleviated left ventricular remodeling and function, and decreased myocardial fibrosis, hypertrophy, and inflammation. Modulating cMSC PDGF receptor expression may thus represent a novel approach to limit pathologic cardiac fibrosis in HF.