Role of Endothelial Progenitor Cells and Inflammatory Cytokines in Healing of Diabetic Foot Ulcers

Abstract

BackgroundTo evaluate changes in endothelial progenitor cells (EPCs) and cytokines in patients with diabetic foot ulceration (DFU) in association with wound healing. MethodsWe studied healthy subjects, diabetic patients not at risk of DFU, at risk of DFU and with active DFU. We prospectively followed the DFU patients over a 12-week period. We also investigated similar changes in diabetic rabbit and mouse models of wound healing. ResultsAll EPC phenotypes except the kinase insert domain receptor (KDR)+CD133+ were reduced in the at risk and the DFU groups compared to the controls. There were no major EPC differences between the control and not at risk group, and between the at risk and DFU groups. Serum stromal-cell derived factor-1 (SDF-1) and stem cell factor (SCF) were increased in DFU patients. DFU patients who healed their ulcers had lower CD34+KDR+ count at visits 3 and 4, serum c-reactive protein (CRP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at visit 1, interleukin-1 (IL-1) at visits 1 and 4. EPCs tended to be higher in both diabetic animal models when compared to their non-diabetic counterparts both before and ten days after wounding. ConclusionsUncomplicated diabetes does not affect EPCs. EPCs are reduced in patients at risk or with DFU while complete wound healing is associated with CD34+KDR+ reduction, suggesting possible increased homing. Low baseline CRP, IL-1α and GM-CSF serum levels were associated with complete wound healing and may potentially serve as prognostic markers of DFU healing. No animal model alone is representative of the human condition, indicating the need for multiple experimental models.

Quality-Quantity Control Culture Enhances Vasculogenesis and Wound Healing Efficacy of Human Diabetic Peripheral Blood CD34+ Cells

“…Protein expression of VEGFR‐1 and 2, implicated in angiogenesis, was lower in diabetic PB‐CD34+ cells, while gene expression was higher when compared to healthy control cells. Similar to our protein KDR expression data, it has been previously reported that the number of CD34+/KDR+ cells is significantly lower in diabetic patients . Diabetic EPCs are reported to have a VEGF‐VEGFR signaling defect, and PCR data for murine EPCs show high VEGFR expression similar to our RT‐qPCR data .…”

Measurements of CD34+/CD45-dim Stem Cells Predict Healing of Diabetic Neuropathic Wounds

“…Analyses were also performed adding the CD133 surface marker for early-generation progenitor cells (33). Because this analysis followed the same pattern as SPCs and added little information, results are not shown.…”

“…One recent report of 29 patients with DFUs found that circulating SPCs with the surface marker CD34 and receptor for the vascular endothelial growth factor-2 decreased over a 12-week time span among those who healed (33). Animal studies have indicated that not only cell number but also content of regulatory proteins such as HIFs influence vasculogenic potential (14,34).…”

Alginate and DNA Gels Are Suitable Delivery Systems for Diabetic Wound Healing

“…9 Moreover, we have shown that both SP 9 and neurotensin (NT) 10,11 modulate inflammation and improve wound healing in DM mouse models. Finally, we have reported reduced numbers of endothelial precursor cells (EPC) in DM patients with complications 12 and shown beneficial effects of EPC transplantation in mouse models of DM wounds 13 and hind limb ischemia. 14 Systemic delivery of drugs is associated with a number of limitations that controlled delivery systems may effectively address.…”