Cell therapy trials suggest that bone marrow (BM)-derived progenitor cells (PCs) could be a promising new option for treating ischemic heart disease, but the efficacy of this approach has been modest. Some of the barriers to successful cell therapy include poor recruitment of cells from the BM to the site of injury and the low proportion of recruited cells that are retained and survive in the ischemic region. Both the release (i.e., mobilization) of PCs from the BM to the peripheral blood and the recruitment and retention of PCs in ischemic tissue are regulated by interactions between stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4), and a recent publication from our laboratory shows that in the BM, SDF-1/CXCR4 signaling is linked to c-kit activity. C-kit is a type III receptor tyrosine kinase and is expressed on the surface of many types of PCs, where it functions as a receptor for stem cell factor (SCF) and is crucial for BM PC- mediated cardiac repair. Our published observations indicate that SDF-1/CXCR4 signaling induces c-kit phosphorylation (transactivation), which retains PCs, in the BM, and that the antagonism or genetic deletion of CXCR4 mobilizes PCs by downregulating SDF-1-mediated (but not SCF-mediated) c-kit activity. We also showed that SDF-1-induced c-kit phosphorylation requires activation of the Src family of non-receptor tyrosine kinases (SFKs)-SFK inhibition blocked both c-kit phosphorylation and the interaction between c-kit and phosphorylated Src in BM PCs-and our ongoing experiments indicate that c-kit-deficiencies impair the migration of BM PCs toward SDF-1 and significantly reduce BM PC recruitment to the ischemic myocardium. The goal of this application is to establish the role of SDF-1/CXCR4-c-kit signaling in BM PC recruitment, and to determine whether techniques that target this pathway could enhance the effectiveness of cell therapy. Our central hypothesis is that SDF-1/CXCR4 signaling activates (i.e., phosphorylates) c-kit, and that c-kit activation subsequently leads to the recruitment and retention of PCs in the ischemic region; thus, treatments that enhance c-kit activity in circulating PCs will improve PC recruitment and PC-mediated cardiac repair by increasing the sensitivity of PCs to SDF-1/CXCR4 signaling. We will accomplish our objective by evaluating our central hypothesis with a series of experiments grouped under three specific aims:
Aim 1) to characterize the molecules and mechanisms involved in SDF-1/CXCR4-c-kit signaling;
Aim 2) to identify the role of SDF- 1/CXCR4-c-kit signaling in BM PC recruitment;
and Aim 3) to determine whether PC recruitment and cardiac repair after MI can be improved by increasing c-kit activity in BM PCs. We anticipate that the work proposed in this project will provide novel insights into the mechanism by which the SDF-1/CXCR4-c-kit pathway regulates BM PC recruitment and retention in ischemic tissue, thereby identifying new therapeutic approaches and targets that could enhance the effectiveness of cell therapy for treatment of ischemic heart disease.
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 stem cells are recruited from the bone marrow to the ischemic heart and, consequently, may identify novel cell-therapy strategies for treating this critical health problem.
|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|
|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|
|Lambers, Erin; Arnone, Baron; Fatima, Anees et al. (2016) Foxc1 Regulates Early Cardiomyogenesis and Functional Properties of Embryonic Stem Cell Derived Cardiomyocytes. Stem Cells 34:1487-500|
|Cheng, Min; Huang, Kai; Zhou, Junlan et al. (2015) A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart. J Mol Cell Cardiol 81:49-53|
|Zhou, Junlan; Cheng, Min; Boriboun, Chan et al. (2015) Inhibition of Sam68 triggers adipose tissue browning. J Endocrinol 225:181-9|
|Wu, Min; Zhou, Junlan; Cheng, Min et al. (2014) E2F1 suppresses cardiac neovascularization by down-regulating VEGF and PlGF expression. Cardiovasc Res 104:412-22|
|Renault, Marie-Ange; Vandierdonck, Soizic; Chapouly, Candice et al. (2013) Gli3 regulation of myogenesis is necessary for ischemia-induced angiogenesis. Circ Res 113:1148-58|
|Zhou, Junlan; Cheng, Min; Liao, Yu-Hua et al. (2013) Rosuvastatin enhances angiogenesis via eNOS-dependent mobilization of endothelial progenitor cells. PLoS One 8:e63126|
|Mackie, Alexander R; Krishnamurthy, Prasanna; Verma, Suresh K et al. (2013) Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function. J Biol Chem 288:18022-34|
Showing the most recent 10 out of 15 publications