The ultimate goal of this study is to improve revascularization therapy for treatment of ischemic disorders. Ischemia in the circulatory system, due to thromboembolism and atherosclerosis, is a major cause of strokes and several cardiovascular diseases. Critical limb ischemia due to injury and chronic disease also leads to limb amputation. These ischemic diseases are clinically treated with drug administration and surgery, which still meet many challenges for the treatment on a permanent basis. Recently, extensive research has focused on revascularization therapies to rebuild the vascular network of the ischemic tissue via angiogenesis, vasculogenesis or both angiogenesis and vasculogenesis, to restore blood perfusion of ischemic tissue.Various stem and progenitor cells in conjunction with several angiogenic cytokines and growth factors are considered promising therapies for revascularization. It is common to transplant stem and progenitor cells via intracoronary injection, but the therapeutic efficacy of the transplanted cells is greatly reduced due to the absence of the signals to guide the cells to the injured endothelium. The objectives of this proposed study are to develop a nano-sized cell guidance molecule and attach it to the transplanted cells, so the transplanted cells can pinpoint the injured endothelium and subsequently improve blood perfusion of ischemic tissue.
We hypothesize that hyper-branched poly(glycerol) modified with epitopes for binding to both transplanted cells and vascular cell adhesion molecules (VCAM)-1 will guide transplanted cells to the injured endothelium because the endothelial injury stimulates endothelial cells to over-express VCAM. Ultimately, this tuning of cell adhesion will significantly improve restoration of blood perfusion in the ischemic tissue. This hypothesis will be examined using the endothelial progenitor cells (EPCs) in the porcine cord blood. The EPCs are extensively being studied for neovascularization because of their potency to secrete angiogenic cytokines and also engraft and form new blood vessels. The oligopeptide containing RGD sequence (RGD peptide) and that containing VHSPNKK sequence (VHSPNKK peptide) will be used as the EPC-binding epitopes and VCAM1-binding epitopes, respectively. The oligopeptide structure will be varied to improve the binding affinity to cells and VCAM-1. These two oligopeptides will be chemically linked to the poly(glycerol).