Identification of E-selectin as a Novel Target for the Regulation of Postnatal Neovascularization
- 1 October 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Annals of Surgery
- Vol. 252 (4), 625-634
- https://doi.org/10.1097/sla.0b013e3181f5a079
Abstract
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.Keywords
This publication has 41 references indexed in Scilit:
- Direct labeling and visualization of blood vessels with lipophilic carbocyanine dye DiINature Protocols, 2008
- Getting to the site of inflammation: the leukocyte adhesion cascade updatedNature Reviews Immunology, 2007
- The Myofibroblast: One Function, Multiple OriginsThe American Journal of Pathology, 2007
- Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1αJCI Insight, 2007
- Fibroblasts in cancerNature Reviews Cancer, 2006
- VEGF‐A and α V β 3 integrin synergistically rescue angiogenesis via N‐Ras and PI3‐K signaling in human microvascular endothelial cellsThe FASEB Journal, 2003
- Fibroblast‐dependent differentiation of human microvascular endothelial cells into capillary‐like, three‐dimensional networksThe FASEB Journal, 2002
- Myofibroblasts and mechano-regulation of connective tissue remodellingNature Reviews Molecular Cell Biology, 2002
- Mechanism of Human Stem Cell Migration and Repopulation of NOD/SCID and B2mnull NOD/SCID MiceAnnals of the New York Academy of Sciences, 2001
- Purification of Recombinant Adeno-Associated Virus Vectors by Column Chromatography and Its Performancein VivoHuman Gene Therapy, 2000