Enhancing EPC Metabolism and Differentiation for Vascular Repair in Diab

    Project: Research project

    Project Details

    Description

    The majority of cell-therapy clinical trials use bone-marrow progenitor cells (BM PCs), but the efficacy remains modest. Major barriers to success include limited potential of PCs to differentiate to endothelial cells (ECs) and functional impairments of PCs from patients’ background disease, such as diabetes that exists in 40-65% of heart failure patients. Recently, we have identified a mechanism by which E2F1 transcription factor may contribute to PC dysfunction. PCs rely primarily on glycolysis for energy supply, and recent reports suggest that their differentiation is triggered by a metabolic switch from glycolysis to oxidative phosphorylation. Our results indicate that E2F1 activates expression of pyruvate dehydrogenase kinase-2 and -4 (PDK2/4) in PCs, that deletion of E2F1 reduces PDK2/4 expression and increases oxygen consumption, that E2F1–/– PCs display a dramatic increases in the capacity for endothelial differentiation. We have also found that significantly greater numbers of ECs are generated when E2F1–/– PCs rather than WT PCs are administered to mice after myocardial infarction. These exciting observations led us to hypothesize that E2F1-mediated metabolic control may prevent adult PCs from responding to angiogenic cues in ischemic tissue and that this metabolic blockade of PC differentiation and vascular repair may be released by E2F1 inhibition. Our goal is to characterize the role and the underlying molecular mechanisms of E2F1-mediated PDK2/4 expression in PC energy metabolism and differentiation (Aim 1), and to determine whether approaches that target this pathway could enhance the effectiveness of PC therapy for ischemic heart disease with concurrent diabetes (Aim 2).
    StatusFinished
    Effective start/end date1/1/1512/31/17

    Funding

    • American Diabetes Association (1-15-BS-148)

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