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

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.

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.

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.