Hyperoxia, Endothelial Progenitor Cell Mobilization, and Diabetic Wound Healing

Abstract

Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic wounds of the lower extremity and diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and wound-level numbers are decreased in diabetes, implicating an abnormality in EPC mobilization and homing mechanisms. The deficiency in EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM). Hyperoxia, induced by a clinically relevant hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to wound tissues. This is partly a result of downregulated production of SDF-1␣ in local wound lesions with diabetes. Administration of exogenous SDF-1␣ into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, neovascularization, and wound healing.

The Role of Synthetic Extracellular Matrices in Endothelial Progenitor Cell Homing for Treatment of Vascular Disease

“…45 The mobilization of EPCs involves key signals that direct EPCs to migrate out of the stem cell niche of the BM and into peripheral circulation. Whereas the molecular mechanisms of leukocyte homing to sites of inflammation are well characterized, those of EPC migration to sites of ischemia and neovascularization are still not fully understood.…”

“…2,25,43,85 VEGF, a key growth factor involved in both angiogenesis and vasculogenesis, has been shown to mobilize BM-derived progenitors into circulation. 5,45 A central chemokine involved in EPC homing, SDF-1, is also produced within the hypoxic stem cell niches of the BM and mediates chemotaxis of various cell types that express the receptor CXCR4. 1,37,45,49 As such, the balance between SDF-1a concentration gradients and CXCR4 expression is thought to determine whether cells home to and stay within niches of the BM or mobilize into peripheral circulation.…”

“…5,45 A central chemokine involved in EPC homing, SDF-1, is also produced within the hypoxic stem cell niches of the BM and mediates chemotaxis of various cell types that express the receptor CXCR4. 1,37,45,49 As such, the balance between SDF-1a concentration gradients and CXCR4 expression is thought to determine whether cells home to and stay within niches of the BM or mobilize into peripheral circulation. 1,49 This SDF-1a/ CXCR4 axis is considered one of the most broadly conserved migratory pathways involved in stem cell mobilization and homing.…”

“…21,51 In such pathological conditions, the ability for EPCs to follow the natural homing cues is impaired partly due to diminished cytokine production and/or an imbalance in factor distribution. 31,45 For instance, high glucose exposure has been shown to promote EPC senescence and endothelial dysfunction. 17 SDF-1 production is also decreased in diabetic wounds, wherein exogenous administration of recombinant SDF-1 was shown to restore EPC recruitment in mice.…”

“…31,46 EPC mobilization and homing is a multi-step process involving detachment from their steady state bone marrow (BM) niches, entry into circulation, rolling along vessel endothelium, transmigration, and adhesion to denuded extracellular matrix (ECM) where they may participate in neovessel formation. 45,73 All of these processes are under the tight regulation of chemokines and their receptors. However, these mechanisms are often interrupted in pathological conditions partly due to matrix modulation and an imbalance in factor presentation at the tissue level.…”