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Published on: January 6, 2018
E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells
Shiyue Xu1, Jun Tao1, Liu Yang1
1From the Department of Biomedical Engineering, Molecular Cardiology Program, School of Medicine and School of Engineering, University of Alabama at Birmingham (S.X., L.Y., E.Z., C.B., G.Q.); Feinberg Cardiovascular Research Institute (S.X., J.Z., T.S., D.W.L., G.Q.) and Department of Medicine - Pulmonary and Critical Care Medicine (N.S.C.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Hypertension and Vascular Disease, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China (S.X., J.T.); Department of Cardiology (L.Y., M.C., K.H.) and Department of Cardiovascular Surgery (J.S., N.D.), Union Hospital of Huazhong University of Science and Technology Tongji Medical College, Wuhan, China; Institute for Medical Biology and Hubei Provincial Key Laboratory for Protection and Application of Special Plants in Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China (Q.L.); Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, RI (T.C.Z.); Department of Basic Science, School of Medicine, Loma Linda University, CA (H.Q.); and Roudebush VA Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (R.A.H.).
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 revascularization after 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 deficient) in mouse BM PCs increases oxidative metabolism and reduces lactate production, resulting in enhanced endothelial differentiation. The metabolic switch in E2F1-deficient BM PCs is mediated by a reduction in the expression of pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase kinase 2; overexpression of pyruvate dehydrogenase kinase 4 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.
Conclusion:
Our results suggest a novel mechanism by which E2F1 mediates the metabolic control of BM PC differentiation, and strategies that inhibit E2F1 or enhance oxidative metabolism in BM PCs may improve the effectiveness of cell therapy.
Insights
Inhibiting E2F1 in bone marrow progenitor cells (BM PCs) enhances their differentiation into endothelial cells by boosting oxidative metabolism. This improves cardiac function after myocardial infarction, offering a new strategy for cardiovascular cell therapy.
Area of Science:
- Cardiovascular Research
- Cell Biology
- Metabolic Regulation
Background:
- Current cardiovascular cell therapy using bone marrow progenitor cells (BM PCs) shows limited efficacy.
- A key barrier is the restricted differentiation of BM PCs into endothelial-lineage cells.
- E2F transcription factor 1 (E2F1) has been identified as a repressor of revascularization.
Purpose of the Study:
- To investigate the role of E2F1 in regulating BM PC function.
- To determine if modulating E2F1 impacts endothelial differentiation and therapeutic potential.
Main Methods:
- Investigated the effects of E2F1 ablation in mouse BM PCs.
- Analyzed metabolic changes, including oxidative metabolism and lactate production.
- Examined the expression of pyruvate dehydrogenase kinase (PDK) isoforms.
- Assessed the impact of E2F1 deletion on cardiac function and vascularization in a myocardial infarction model.
Main Results:
- E2F1 deficiency in BM PCs increased oxidative metabolism and reduced lactate production, promoting endothelial differentiation.
- Reduced expression of PDK4 and PDK2 mediated this metabolic shift.
- Overexpression of PDK4 reversed the enhanced oxidative metabolism and endothelial differentiation.
- E2F1 deletion in BM PCs improved vascular growth, reduced infarct size, and enhanced cardiac function post-myocardial infarction.
Conclusions:
- E2F1 acts as a repressor of BM PC endothelial differentiation through metabolic control.
- Inhibiting E2F1 or enhancing oxidative metabolism in BM PCs represents a novel strategy to improve cardiovascular cell therapy efficacy.
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