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). Our preliminary observations indicate that SDF-1/CXCR4 signaling induces Src family of non-receptor tyrosine kinases (SFKs)—SFK phosphorylation, which retains PCs in the BM, and that SFK inhibition blocked SDF-1/CXCR4–mediated recruitment of BM progenitor cells to the ischemic myocardium. We hypothesize that SDF-1/CXCR4 signaling activates (i.e., phosphorylates) SFK, and that SFK activation subsequently leads to the recruitment and retention of PCs in the ischemic region; thus, treatments that enhance SFK activity in circulating PCs will improve PC recruitment and PC-mediated cardiac repair by increasing the sensitivity of PCs to SDF-1/CXCR4 signaling. The three objectives of this proposal are 1) to determine the role of SDF-1/CXCR4–SFK signaling in BM PC recruitment to the ischemic myocardium, 2) to elucidate the molecular mechanisms responsible for SDF-1/CXCR4–SFK pathway mediated BM PC recruitment, and 3) to investigate whether increasing SFK activity in BM PCs can improve cardiac repair after MI. We anticipate that the work proposed in this project will provide novel insights into the mechanism by which the SDF-1/CXCR4–SFK 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.
|Effective start/end date||7/1/13 → 6/30/18|
- American Heart Association (13SDG17120011)