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.Keywords: CCL, C-C motif chemokine ligand; CCR2, C-C chemokine receptor 2; DDR2, discoidin domain receptor 2; DMEM, Dulbecco’s modified Eagle medium; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; HF, heart failure; IL, interleukin; INF, interferon; LV, left ventricular; Lin, lineage; MI, myocardial infarction; MSC, mesenchymal stem cell; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; TGFβ, transforming growth factor beta; WGA, wheat germ agglutinin; cDNA, complementary DNA; cMSC, cardiac mesenchymal stem cell; cardiac remodeling; fibrosis; heart failure; mRNA, messenger RNA; mesenchymal stem cells; myocardial inflammation; myofibroblasts; platelet-derived growth factor receptor; siRNA, small interfering RNA; α-SMA, alpha smooth muscle actin.