E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells
Rationale: The majority of current cardiovascular cell-therapy trials use bone marrow progenitor cells (BM PCs) and achieve only modest efficacy; the limited potential of these cells to differentiate into endothelial-lineage cells is one of the major barriers to the success of this promising therapy. We have previously reported that the E2F transcription factor 1 (E2F1) is a repressor of neovascularization following ischemic injury.
Objective: We sought to define the role of E2F1 in the regulation of BM PC function.
Methods and Results: Ablation of E2F1 (E2F1-/-) in mouse BM PCs increases oxidative metabolism and reduces lactate production, resulting in enhanced endothelial differentiation. The metabolic switch in E2F1-/- BM PCs is mediated by a reduction in the expression of pyruvate dehydrogenase kinase 4 (PDK4) and PDK2; overexpression of PDK4 reverses the enhancement of oxidative metabolism and endothelial differentiation. Deletion of E2F1 in the BM increases the amount of PC-derived endothelial cells in the ischemic myocardium, enhances vascular growth, reduces infarct size, and improves cardiac function after myocardial infarction.
Conclusions: Our results suggest a novel mechanism by which E2F1 mediates the metabolic control of BM PC differentiation, and strategies that inhibit E2F1 and/or enhance oxidative metabolism in BM PCs may improve the effectiveness of cell therapy.
- Oxidative metabolism
- bone marrow progenitor cell
- endothelial progenitor cells
- myocardial infarction
- stem cell
- oxygen consumption
- Received August 1, 2017.
- Revision received December 18, 2017.
- Accepted January 19, 2018.