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Global and Endothelial Cell Specific Deletion of SDF-1 Results in Delayed Wound Healing
Zeshaan N. Maan, MBBS, MS, MRCS1, Natalie Ho, High school1, Robert C. Rennert, BA1, Dominik Duscher, MD1, Michael Sorkin, MD1, Melanie Rodrigues, PhD1, Jerry Chen, MD1, Ivan N. Vial, MD2, Michael Januszyk, MD1, Michael Findlay, MBBS, PhD1, Michael Hu, MD1, Graham Walmsley, BA1, Michael T. Longaker, MD, MBA1, Geoffrey C. Gurtner, MD, FACS1.
1Stanford University School of Medicine, Stanford, CA, USA, 2University of Pittsburgh, Pittsburgh, PA, USA.
Chronic, poorly healing wounds remain a significant problem in clinical practice, especially in the elderly and patients with diabetes mellitus. Poor neovascularization is thought to be fundamental to this problem. Stromal-derived factor-1 (SDF-1) is a chemokine involved in neovascularization and thought to play a major role in trafficking progenitor cells to ischemic tissue, under a HIF-1α dependent mechanism. Recent studies have found that diabetics and the elderly are deficient in SDF-1, suggesting a possible mechanism for poor wound healing. To better understand the role of SDF-1 in this setting, we studied the effect of global (gKO) and endothelial cell-specific SDF-1 knockout (eKO) on wound healing and cell behavior, utilizing newly developed murine models.
A humanized excisional wound was created on the dorsum of gKO, eKO and wild type mice. Wounds were photographed and assessed at regular intervals. Tissue was harvested for histology and qRT-PCR. The excisional wound model was repeated in eKO and WT mice parabiosed to GFP+ reporter mice to assess recruitment of circulating progenitor cells.
The eKO and gKO groups both demonstrated slower wound healing, 15 days to closure compared with 11.75 in control mice (*p=0.006). This effect became evident by day 8, with significantly increased mean wound area relative to original size (control = 27%; gKO = 59%, *p=0.02; eKO = 55%, *p=0.03)(Figure 1). WT mice demonstrated increased recruitment of circulating progenitor cells (GFP+, Lin-, CD64-) to wounds compared to eKO mice (*p<0.001). qRT-PCR demonstrated reduced transcription of SDF-1 (*p=0.002), epidermal growth factor (EGF) (*p=0.002), vascular endothelial growth factor (VEGF) (*p=0.03) and fibroblast growth factor-2 (FGF-2) (*p=0.02) in eKO mice v WT. Immunofluorescence studies demonstrated reduced expression of SDF-1 (*p=0.008), VEGF (*p<0.05), FGF-2 (*p=0.006) and CD31 (*p=0.02) in eKO mice (Figure 2).
SDF-1 plays a pivotal role in the wound healing response, particularly SDF-1 expression from endothelial cells. The importance of endothelial cell production of SDF-1 in wound healing is related to support of local cytokine expression, recruitment of circulating progenitor cells and promotion of neovascularization. Further investigation of these knockout models is ongoing to better elucidate the biology of SDF-1 within wounds.
Figure 1: eKO and gKO mice demonstrated similarly delayed wound healing.
Figure 2: eKO mice demonstrate reduced SDF-1, VEGF and FGF-2 at Day 7 post-wounding and reduced neovascularization at Day 14.
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