title: Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Runxia
authors.initials: R
authors.lastname: Tian
authors.forename: Weijun
authors.initials: W
authors.lastname: An
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhuge
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Shao
authors.forename: Bianca
authors.initials: B
authors.lastname: Habib
authors.forename: Alan S
authors.initials: AS
authors.lastname: Livingstone
authors.forename: Omaida C
authors.initials: OC
authors.lastname: Velazquez
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D000229:Dependovirus; D003920:Diabetes Mellitus / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D019040:E-Selectin / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D019040:E-Selectin