The majority of ongoing cell-therapy trials for ischemic heart disease (IHD) use bone marrow (BM)-derived progenitor cells (PCs); however, the efficacy remains modest. Major barriers to effective cell therapy include limited potential of PCs to differentiate to ECs and functional impairments of PCs from patients' background disease, such as diabetes which accounts for 40-65% of heart failure patients in the US. Recently we found that the E2F1 transcription factor contributes to EPC dysfunction in diabetic conditions by activating the expression of pyruvate dehydrogenase kinases 2 and 4 (PDK2/4). Deletion of E2F1 (E2F1-/-) in BM PCs leads to reduced PDK2/4 expression and increased oxygen consumption. These results are extremely exciting because PCs normally reside in their niche at a relatively quiescent state and rely primarily on glycolysis as fuel source (even with sufficient oxygen supply), and recent reports suggest that a metabolic switch from glycolysis to oxidative phosphorylation is required for their functional activation and differentiation. Indeed, we found that the altered metabolic activities in E2F1-/- PCs are associated with a dramatic increase in the capacity of endothelial differentiation. Remarkably, after administered to mice with myocardial infarction, E2F1-/- PCs generated significantly more ECs in the ischemic myocardium than WT PCs. Furthermore, we have identified that Sam68, an adaptor protein involved in high-fat diet (HFD) - induced insulin resistance, interacts with E2F1 and enhances E2F1-mediated PDK2/4 promoter activity. Collectively, accumulating evidence in the literature indicates that adult BM PCs, when recruited at sites of injury, are not readily differentiating int vascular cells despite the environmental angiogenic cues, and our results suggest that this checkpoint is enforced, at least partially, by E2F1-mediated metabolic control; thus inhibition o E2F1 may re-set the metabolic switch to permit PC differentiation and vascular repair. The goal of this application is to establish the role of the E2F1-PDK2/4 pathway in BM PC energy metabolism and differentiation, and to determine whether approaches that target this pathway could enhance the effectiveness of BM PC therapy for IDH with concurrent diabetes. Our central hypothesis is that E2F1 activates PDK2/4 expression, thus inhibiting glucose utilization and PC differentiation in ischemic reperfused heart, and that targeted inhibition of the E2F1-PDK2/4 pathway can promotes PC differentiation and cardiovascular repair. A series of experiments are proposed to (Aim 1) characterize the role and the underlying molecular mechanisms of E2F1-mediated PDK2/4 expression in the regulation of BM PC metabolism, differentiation, and function and to (Aim 2) evaluate the effectiveness of targeting the E2F1- PDK2/4 pathway for enhancement of BM PC recruitment, differentiation, and PC-mediated cardiovascular repair. We expect that this study will advance the field by establishing the crucial role of cellular metabolim in BM PC differentiation and opening new avenues into research for better cardiovascular cell therapy.
Ischemic heart disease, the leading cause of death nationally, occurs when vessels are unable to deliver a sufficient supply of blood to the heart, which also limits the capacity of the heart to regenerate tissues damaged by a cardiovascular event or disease. This proposal describes a series of experiments that will help unravel the mechanisms by which bone marrow stem cells differentiate to new vessels in the ischemic heart and, consequently, may identify novel cell- therapy strategies for treating this critical health problem
| Zhou, Shanshan; Wang, Jiqun; Yin, Xia et al. (2018) Nrf2 expression and function, but not MT expression, is indispensable for sulforaphane-mediated protection against intermittent hypoxia-induced cardiomyopathy in mice. Redox Biol 19:11-21 |
| Xu, Shiyue; Tao, Jun; Yang, Liu et al. (2018) E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells. Circ Res 122:701-711 |
| Arnone, Baron; Chen, Jake Y; Qin, Gangjian (2017) Characterization and analysis of long non-coding rna (lncRNA) in In Vitro- and Ex Vivo-derived cardiac progenitor cells. PLoS One 12:e0180096 |
| Zhao, Ming (2016) Innovative reporter gene imaging techniques making inroads to biology. Cardiovasc Res 112:617-618 |
| Wang, Ningning; Wu, Yiping; Zeng, Ning et al. (2016) E2F1 Hinders Skin Wound Healing by Repressing Vascular Endothelial Growth Factor (VEGF) Expression, Neovascularization, and Macrophage Recruitment. PLoS One 11:e0160411 |
