A variety of sterile diseases, including myocardial infarction (MI) and subsequent repair, involve the immune system. Although unresolved inflammation exacerbates heart failure, depletion of macrophages in the infarcted myocardium leads to left ventricular (LV) rupture and death. Thus, indiscriminate immunosuppression is not a viable approach. Nevertheless, persistent inflammation in the failing heart must be addressed. Unfortunately, significant barriers to progress remain because we do not know how immune cells regulate myocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a unique opportunity for understanding how immune cells contribute to myocardial repair, and recent findings implicate macrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cells survive long-term in the recipient, common benefits include reduction of fibrosis, enhanced angiogenesis, and improvement in LV function. These improvements occur independently of differentiation of the injected cells into cardiomyocytes, suggesting that cell therapy must recruit endogenous repair mechanisms; however, these mechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarcted heart promotes accumulation of reparative macrophages, decreases fibrosis, and improves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program, and it may be due to CMC-derived bioactive lipids—such as prostaglandins, leukotrienes, and resolvins— which offer testable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus, we propose that CMCs recruit monocytes and activate reparative macrophages, which promote favorable anti-fibrotic cardiac remodeling and improve cardiac function in the infarcted heart. In the current project we will determine the capacity for the bioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role of Cox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactive lipids in macrophage recruitment and their reparative function, with the particular focus on macrophage BLT-1 receptor and its CMC-derived ligands. Finally, we will determine the reparative effect of CMCs with enhanced bioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactive lipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways of bioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.