Chronic heart failure (HF) is characterized by inflammation, macrophage infiltration, and progressive fibrosis. Along with fibroblasts, mesenchymal stem cells (MSCs) can differentiate into pro-fibrotic myofibroblasts. Platelet derived growth factor (PDGF), induced in response to inflammation, is a known regulator of tissue fibrosis and angiogenesis, and both macrophages and MSCs secrete PDGF and express PDGF receptors (PDGFRs). We hypothesized that PDGF signaling in cardiac-resident MSCs (cMSCs) promotes their myofibroblast differentiation and thereby aggravates LV remodeling and fibrosis after myocardial infarction (MI). Sca1+CD90+CD31-DDR2- cMSCs were isolated from tissue explants of mouse hearts 8 w after either sham operation (control) or coronary ligation (HF) and maintained in culture. Compared with sham cMSCs, HF cMSCs exhibited higher PDGF and PDGFR levels and pro-inflammatory secretory profiles. Co-culture with pro-inflammatory M1 macrophages further augmented PDGF expression and promoted myofibroblastic differentiation in HF cMSC but not sham cMSCs, as assessed by gel contraction assays and gene expression. PDGFR inhibition by imatinib (10 μM) treatment blocked HF-cMSC myofibroblast differentiation and instead induced an endothelial phenotype. In parallel studies, C57BL/6 mice (4/group) were treated 2 w after coronary ligation with either PBS (control) or imatinib (30 mg/kg) i.v daily for 3 w. Echocardiography revealed that after 3 w, PBS-injected mice exhibited progressive LV dysfunction (EF 17 ± 9 vs. 25 ± 8% pre-treatment, p < 0.05) and dilatation (EDV 158 ± 60 vs. 114 ± 28 mL, p < 0.05). In contrast, imatinib treatment stabilized cardiac function (EF 19 ± 5 vs. 20 ± 5%, p= NS) and size (EDV 119 ± 34 vs. 110 ± 38 mL, p= NS) over this period. These effects occurred together with decreased border zone fibrosis in imatinib-treated mice, as assessed by trichrome staining (12 ± 3 vs. 29 ± 7%). We conclude that augmented cMSC-localized PDGF signaling in response to the inflammatory milieu after MI channels cMSCs towards a myofibroblastic fate (and away from an endothelial cell fate), thereby promoting fibrosis, adverse cardiac remodeling, and the progression of post-MI HF.Author Disclosures: T. Hamid: None. Y. Xu: None. M.A. Ismahil: None. S.S. Bansal: None. S.D. Prabhu: None.