Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing.

OBJECTIVES: We previously reported that stromal cell-derived factor-1α (SDF-1α, a homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds (Gallagher et al, J Clin Invest. 2007;117:1249-1259). We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1α-mediated EPC homing. METHODS: SDF-1α in diabetic wounds were therapeutically increased by injection of SDF-1α-engineered bone marrow-derived fibroblasts versus control cells (N = 48 [20, non-obese diabetic (NOD)], [28, streptozotocin-C57]). Polymerase chain reaction-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1α-induced EPC homing, and wound healing was furthered studied using antagonists in vitro and in vivo. RESULTS: Increasing wound SDF-1α via cell-based therapy promotes healing in diabetic mice (∼20% increase in healing rates by day 3, P = 0.006). SDF-1α increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular EC (2.3-fold increase, P < 0.01). This effect was also significant in blood vessels of the experimental mice and resulted in increased wound neovascularization. The regulatory effects of SDF-1α on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1α-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing. CONCLUSIONS: SDF-1α-engineered cell-based therapy promotes diabetic wound healing in mice by specifically upregulating E-selectin expression in mature EC leading to increase EC-EPC adhesion, EPC homing, and increased wound neovascularization. These findings provide novel insight into the signals underlying the biological effect of SDF-1α on EPC homing and point to E-selectin as a new potential target for therapeutic manipulation of EPC trafficking in diabetic wound healing.

Diabetic foot ulcers: effects of hyperoxia and SDF-1α on endothelial progenitor cells.

Diabetes mellitus is a common disease afflicting many people. In addition to coronary artery disease, diabetic retinopathy and renal failure, diabetic patients face abnormal wound healing and have increased lower extremity ulcers and amputations. In diabetes, wound healing is altered due to both macrovascular and microvascular processes. While the former can be addressed with surgical intervention, the latter is more difficult to correct. Neovascularization within the granulation tissue via angiogenesis and vasculogenesis is critical for wound healing. Endothelial progenitor cells (EPCs) have been implicated in vasculogenesis. Mobilization of EPCs from the bone marrow is impaired in diabetes and homing of EPCs to the wound is also abnormal. Recent studies show that hyperoxia and administration of exogenous stromal-derived factor-1α increases circulatory and wound levels of EPCs and improves wound healing in diabetic mice. These findings have great potential for translation into human counterparts as the treatment for this prevalent disease matures.