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

Abstract

Objective Impaired diabetic wound healing is associated with abnormal 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. Design of study Db/Db diabetic mice and Db/+ non-diabetic mice were wounded with an 8mm punch biopsy and the wounds treated with a lentiviral vector containing either the 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 PCR. The effect of the SDF-1α inhibitor on cellular migration was also assessed. Results Inhibition of SDF-1α resulted in a significant decrease in the rate of diabetic wound healing, (3.8 cm2/day versus 6.5 cm2/day in GFP-treated wounds p=0.04), and also impaired the early phase of non-diabetic wound healing. SDF-1α inhibition also resulted in fewer small-caliber vessels, less granulation tissue formation, and increased proinflammatory gene expression (IL-6 and MIP-2) in the diabetic wounds. Conclusions The 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.

Cancer-Associated Fibroblasts Drive the Progression of Metastasis through both Paracrine and Mechanical Pressure on Cancer Tissue

“…49). Myofibroblasts secrete a potent chemokine, the stromal-derived factor-1 (SDF-1), also known as CXCL12, which assists in the recruitment of EPCs at the wound site (50). Once EPCs are chemotactically attracted, they may transdifferentiate into endothelial cells with the assistance of VEGF, also secreted by myofibroblasts (51, 52).…”

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…141 A relative lack of CXCL12, as found in diabetic wounds, lead to decreased cellular migration and angiogenesis as well as increased inflammation. 142 During diabetic wound healing, administration of CXCL12 directly to the wound reversed EPC recruitment impairment in mice. 143 This beneficial effect has been replicated by lentiviral-mediated gene transfer of CXCL12 in diabetic mice wounds resulting in improved early healing.…”

Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

“…SDF-1α participates in angiogenesis by stimulating endothelial cells to express VEGF and synergistically promoting the recruitment of endothelial progenitor cells to wounds (21). Suppression of SDF-1α leads to decreased numbers of vascular vessels and granulation tissues and aggravation of the inflammatory response, severely impairing the normal wound healing process (22); therefore, Akt/HIF-1α signaling and downstream pro-angiogenic factors play a critical role in the progression of diabetic wound healing. In the present study, expression of the Akt/HIF-1α axis and downstream genes was decreased in the T1DM mice prior to wound formation, which could explain the reduced angiogenesis and the delay in wound healing.…”