Objective: To characterize cardiac mesenchymal stem cells (cMSCs) and define the role of platelet derived growth factor receptor (PDGFR) signaling on cMSC-myofibroblast differentiation. To evaluate the in vivo effects of PDGFR inhibition on the outcomes of post-myocardial infraction (MI) cardiac remodeling, function and inflammation. Background: Heart failure (HF) is characterized by chronic inflammation, fibrosis, and activation of pro-fibrotic myofibroblasts. PDGF is a known regulator of fibrosis while PDGFR is a marker of MSCs. In addition to fibroblasts, tissue MSCs also differentiate into myofibroblasts; however, the contribution of cMSCs and cMSC-localized PDGFR to fibrosis in the failing heart is unknown. Methods: Flow cytometry was used to quantitate cMSCs in failing hearts. Multiple in vitro experiments were used to characterize cMSCs. Permanent coronary ligation in mice was used to induce myocardial infarction and failure while echocardiography was used asses cardiac function. Results: We demonstrate that; 1) cMSCs temporally expand post-MI and acquire a pro-inflammatory and a pro-fibrotic cell fate, 2) pro-inflammatory macrophages promote a PDGFR-dependent pro-fibrotic myofibroblast differentiation fate specifically in HF-derived cMSCs, and that, 3) inhibition of PDGFR signaling in vivo attenuates post-MI LV remodeling and function. These in vivo effects occurred concomitantly with decreased myocardial fibrosis, myocyte hypertrophy and reduced myocardial infiltration of pro-inflammatory macrophages. Conclusion: Our findings suggest that restoring or maintaining a normal cMSC phenotype by modulating PDGFR expression and/or activation may represent a novel approach for both combating pathological fibrosis in the failing heart as well as potentially enhancing cardiac repair upon exogenous cMSC transplantation in HF.