Inhibition of stromal cell-derived factor-1α further impairs diabetic wound healing

ObjectiveImpaired diabetic wound healing is associated with abnormal stromal cell-derived factor (SDF)-1α production, decreased angiogenesis, and chronic inflammation. Lentiviral-mediated overexpression of SDF-1α can correct the impairments in angiogenesis and healing in diabetic wounds. We hypothesized that SDF-1α is a critical component of the normal wound-healing response and that inhibition of SDF-1α would further delay the wound-healing process.MethodsdB/Db diabetic mice and Db/+ nondiabetic mice were wounded with an 8-mm punch biopsy and the wounds treated with a lentiviral vector containing either the green fluorescent protein (GFP) or SDF-1α inhibitor transgene. The inhibitor transgene is a mutant form of SDF-1α that binds, but does not activate, the CXCR4 receptor. Computerized planimetry was used to measure wound size daily. Wounds were analyzed at 3 and 7 days by histology and for production of inflammatory markers using real-time polymerase chain reaction. The effect of the SDF-1α inhibitor on cellular migration was also assessed.ResultsInhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 vs 6.5 cm2/day in GFP-treated wounds; P = .04), and also impaired the early phase of nondiabetic wound healing. SDF-1α inhibition resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression of interleukin-6 and macrophage inflammatory protein-2 in the diabetic wounds.ConclusionsThe relative level of SDF-1α in the wound plays a key role in the wound-healing response. Alterations in the wound level of SDF-1α, as seen in diabetes or by SDF-1α inhibition, impair healing by decreasing cellular migration and angiogenesis, leading to increased production of inflammatory cytokines and inflammation. Inhibition of SDF-1α further impairs diabetic wound healing.

Clinical RelevanceDiabetes results in a significant impairment in wound healing, leading to significant morbidity and health care expenditures. The pathophysiology that underlies this process is multifactorial, including abnormal growth factor production, cellular migration, and cellular function. Stromal cell-derived factor (SDF)-1α is a key chemokine involved in the wound-healing process and is involved in cellular recruitment and angiogenesis. SDF-1α is decreased in diabetic individuals. This study showed that inhibition of SDF-1α results in an even more dramatic delay in the diabetic wound-healing process and even results in a delay in the early phases of wound healing in normal mice, further supporting its role in wound healing. Inhibition of this chemokine promotes greater inflammatory cytokine production, inflammatory cell migration, and less vasculogenesis after dermal wounding. This study identifies SDF-1α as an essential component of normal wound healing and provides a potential therapeutic target to improve the diabetic wound-healing impairment.