Identification of E-Selectin as a Novel Target for the Regulation of Post-Natal Neovascularization: Implications for Diabetic Wound Healing
*Zhao-Jun Liu, *Runxia Tian, *Weijun An, *Ying Zhuge, *Yan Li, *Hongwei Shao, *Bianca Habib, Alan S Livingstone, *Omaida C Velazquez
University of Miami, Miami, FL
Objectives: We previously reported that stromal cell-derived factor-1alpha (SDF-1a; homing signal for recruiting endothelial progenitor cells (EPC) to areas of neovascularization), is down-regulated in diabetic wounds (J Clin Invest, 2007). We now investigate signals whereby mature endothelial cells (EC) and circulating EPC achieve SDF-1a-mediated EPC homing.
Methods: SDF-1a levels in diabetic wounds were therapeutically increased by injection of SDF-1a-engineered bone marrow-derived fibroblasts versus control cells (N= 48 (20, NOD), (28, STZ-C57)). PCR-array gene expression differences were validated by Western blotting and immunohistochemistry. The role of adhesion molecule(s) in mediating SDF-1a-induced EPC homing and wound healing was furthered studied using antagonists in vitro and in vivo.
Results: Increasing wound SDF-1a via cell-base therapy promotes healing in diabetic mice (20% increase, P=0.006). SDF-1a increased EC-EPC adhesion and specifically upregulated E-selectin expression in human microvascular ECs (4.6-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-1a on EC-EPC adhesion and EPC homing were specifically mediated by E-selectin, as the application of E-selectin antagonists significantly inhibited SDF-1a-induced EC-EPC adhesion, EPC homing, wound neovascularization, and wound healing.
Conclusions: SDF-1a-engineered cells promote diabetic wound healing in mice by specifically upregulating E-selectin expression in mature ECs leading to increase EC-EPC adhesion, EPC homing and increased wound neovascularization. These findings provide novel insight into the signals underlying the effect of SDF-1a on EPC homing and point to E-selectin as new potential target for therapeutic manipulation of EPC traffic in diabetic wound healing.