Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Endothelial CXCL12 Recruits a Novel Circulating Progenitor Cell in Response to Tissue Injury
Zeshaan N. Maan, MBBS, MSc, MRCS, Dominik Duscher, MD, Alexander J. Whittam, BA, I N. Vial, MD, Michael Januszyk, MD, PhD, Lauren Fischer, MD, Robert C. Rennert, MD, Melanie Rodrigues, PhD, Michael S. Hu, MD, MS, MPH, Graham G. Walmsley, BA, Michael T. Longaker, MD, MBA, Geoffrey C. Gurtner, MD, FACS.
Stanford University School of Medicine, Stanford, CA, USA.

PURPOSE:
An impaired neovascular response underlies the significant cardiovascular complications seen in elderly and diabetic patients. Stromal-derived factor-1 (SDF-1), a cytokine primarily known for its chemotactic function is also thought to play a role in neovascularization. Recent studies have found that diabetics and the elderly are deficient in SDF-1, suggesting a possible mechanism for their cardiovascular complications. Utilizing newly developed murine models, we studied the effect of global (gKO) and endothelial cell-specific SDF-1 knockout (eKO) during wound healing and neovascularization.
METHODS:
Humanized excisional wounds were created on the dorsum of gKO, eKO and wild type mice. An ischemic skin flap was created on the dorsum of eKO and WT mice. Wounds and flaps were photographed and assessed at regular intervals. Parabiosis and microfluidic based single cell gene expression analysis was used to interrogate the recruitment of putative circulating progenitor cells (CPCs) by endothelial SDF-1.
RESULTS:
The eKO and gKO groups demonstrated similarly impaired wound healing (*p=0.006). eKO wounds had reduced transcription and protein expression of SDF-1 (*p=0.002; *p=0.008), vascular endothelial growth factor (VEGF) (*p<0.05; *p<0.05) and fibroblast growth factor-2 (FGF-2) (*p<0.05; *p=0.006) with decreased vascular density (*p<0.05). eKO mice also had reduced ischemic flap survival (39% v 72%; *p=0.008) associated with decreased vascular density (*p=0.003). Parabiosis demonstrated decreased recruitment of CPCs to eKO wounds compared to control (*p<0.001). Microfluidic single cell analysis of recruited CPCs identified a distinct subpopulation, with an angiogenic profile, critically recruited by SDF-1 (Figure 1).
CONCLUSIONS:
Endothelial cell SDF-1 (eSDF-1) represents an important therapeutic target, as it plays a pivotal role in neovascularization of ischemic tissue. eSDF-1 regulates the expression of angiogenic cytokines and subsequent neovascularization of ischemic tissue. This is likely related to its role in CPC recruitment as a distinct angiogenic circulating progenitor cell is exclusively recruited by eSDF-1.


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