It has been estimated that up to 2 million Americans suffer from non-healing lower extremity wounds, most as a complication of Diabetes. Bone marrow-derived endothelial progenitor cells (BMD EPC) contribute to wound healing since these progenitor/stem cells are the key cellular effectors of post-natal vasculogenesis. BMD EPC are deficient in Diabetes. Hyperoxia induced by hyperbaric oxygen (HBO2) treatments is used as a safe, FDA- approved, adjunctive therapy to stimulate wound healing in diabetic patients, but the mechanisms of action are poorly understood and HBO2 is not uniformly effective, particularly in diabetic patients with associated peripheral arterial disease (PAD), accounting for the fact that diabetic/ischemic chronic non-healing lower extremity wounds continue to be an unsolved clinical problem. In preliminary studies, we have determined that hyperoxia, induced by a clinically relevant HBO2 protocol, increases nitric oxide (.NO) levels within femoral bone marrow, accelerates the spontaneous revascularization of surgically induced hindlimb ischemia, and increases the number of BMD EPC in circulation. Additional preliminary studies indicate that Stromal cell- derived growth factor 11 (SDF-1), a chemokine that mediates EPC homing via its receptor CXCR4, is decreased in diabetic wounds and SDF-1 wound-injections partially restores the diabetic defect in wound BMD EPC recruitment, and (together with hyperoxia) synergistically enhances diabetic wound healing. Our overall goal is to develop new strategies for treating patients with chronic wounds of the legs. We hypothesized that hyperoxia induces release of BMD EPC and that these cells may then be recruited into wounds in increased numbers by virtue of their hyperoxia-induced activation and their increased numbers within the blood pool;however, local wound interventions that enhance EPC homing (such as increasing level of EPC homing chemochine, SDF-1) may be crucial for optimal therapeutic recruitment of these progenitor cells to wounds complicated by diabetes and ischemia. We further hypothesized that the delineation of the mechanisms that result in hyperoxia-induced progenitor/stem cell release will serve as the foundation for identifying novel and potentially synergistic targets for further enhancing therapeutic BMD EPC release and their recruitment into non-healing wounds. The specific goals of this research proposal are: 1.To determine the efficacy of hyperoxia (alone and in combination with SDF-1 local wound treatment) for inducing therapeutic EPC release and recruitment into diabetic/ischemic wounds, and determine if that plasma SDF-1 levels are predictive of EPC counts and wound healing in diabetic patients with PAD and in genetic murine models of diabetes. 2. To elucidate the mechanism of progenitor/stem cell mobilization by hyperoxia.In this grant application entitled Recruiting Activated Endothelial Progenitor Cells to Wounds by Hyperoxia &SDF-11 , we propose to study three fundamental questions that if answered may revolutionize the field of wound healing: (1) Is the systemic level of SDF-11 a key predictor of wound healing in diabetic patients with PAD? (2) Can targeted optimal hyperoxia exposures and wound chemokine manipulations heal wounds affected by both diabetes and ischemia? And (3) what are the downstream mechanisms of hyperoxia-induced stem cell mobilization?

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National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Ikeda, Richard A
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Zhuge, Ying; Regueiro, Manuela M; Tian, Runxia et al. (2018) The effect of estrogen on diabetic wound healing is mediated through increasing the function of various bone marrow-derived progenitor cells. J Vasc Surg 68:127S-135S
Liu, Zhao-Jun; Tian, Runxia; Li, Yan et al. (2016) SDF-1?-induced dual pairs of E-selectin/ligand mediate endothelial progenitor cell homing to critical ischemia. Sci Rep 6:34416
Liu, Zhao-Jun; Daftarian, Pirouz; Kovalski, Letícia et al. (2016) Directing and Potentiating Stem Cell-Mediated Angiogenesis and Tissue Repair by Cell Surface E-Selectin Coating. PLoS One 11:e0154053
Castilla, Diego M; Liu, Zhao-Jun; Tian, Runxia et al. (2012) A novel autologous cell-based therapy to promote diabetic wound healing. Ann Surg 256:560-72
Liu, Zhao-Jun; Li, Yan; Tan, Yurong et al. (2012) Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1. PLoS One 7:e38811
Liu, Zhao-Jun; Tan, Yurong; Beecham, Gary W et al. (2012) Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis 225:296-303
Liu, Zhao-Jun; Tian, Runxia; Li, Yan et al. (2011) Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E-selectin. Ann Surg 254:450-6; discussion 456-7
Nedeau, April E; Gallagher, Katherine A; Liu, Zhao-Jun et al. (2011) Elevation of hemopexin-like fragment of matrix metalloproteinase-2 tissue levels inhibits ischemic wound healing and angiogenesis. J Vasc Surg 54:1430-8
Liu, Zhao-Jun; Tian, Runxia; An, Weijun et al. (2010) Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing. Ann Surg 252:625-34
Milovanova, Tatyana N; Bhopale, Veena M; Sorokina, Elena M et al. (2009) Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo. J Appl Physiol 106:711-28

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