E2F1 suppresses oxidative metabolism and endothelial differentiation of bone marrow progenitor cells

Shiyue Xu, Jun Tao, Liu Yang, Eric Zhang, Chan Boriboun, Junlan Zhou, Tianjiao Sun, Min Cheng, Kai Huang, Jiawei Shi, Nianguo Dong, Qinghua Liu, Ting C. Zhao, Hongyu Qiu, Robert A. Harris, Navdeep S. Chandel, Douglas W. Losordo, Gangjian Qin

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)701-711
Number of pages11
JournalCirculation research
Volume122
Issue number5
DOIs
StatePublished - Mar 2018

Keywords

  • Bone marrow
  • Cell differentiation
  • Endothelial progenitor cells
  • Myocardial infarction
  • Oxygen consumption
  • Stem cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Xu, S., Tao, J., Yang, L., Zhang, E., Boriboun, C., Zhou, J., Sun, T., Cheng, M., Huang, K., Shi, J., Dong, N., Liu, Q., Zhao, T. C., Qiu, H., Harris, R. A., Chandel, N. S., Losordo, D. W., & Qin, G. (2018). E2F1 suppresses oxidative metabolism and endothelial differentiation of bone marrow progenitor cells. Circulation research, 122(5), 701-711. https://doi.org/10.1161/CIRCRESAHA.117.311814