Abstract
Diabetes produces a chronic inflammatory state that contributes to the development of vascular disease and impaired wound healing. Despite the known individual and societal impacts of diabetic ulcers, there are limited therapies effective at improving healing. Stromal cell-derived factor 1α (SDF-1α) is a CXC chemokine that functions via activation of the CXC chemokine receptor type 4 (CXCR4) receptor to recruit hematopoietic cells to locations of tissue injury and promote tissue repair. The expression of SDF-1α is reduced in diabetic wounds, suggesting a potential contribution to wound healing impairment and presenting the CXCR4 receptor as a target for therapeutic investigations. We developed a high-throughput β-arrestin recruitment assay and conducted structure–activity relationship (SAR) studies to screen compounds for utility as CXCR4 agonists. We identified CXCR4 agonist UCUF-728 from our studies and further validated its activity in vitro in diabetic fibroblasts. UCUF-728 reduced overexpression of miRNA-15b and miRNA-29a, negative regulators of angiogenesis and type I collagen production, respectively, in diabetic fibroblasts. In vivo, UCUF-728 reduced the wound closure time by 36% and increased the evidence of angiogenesis in diabetic mice. Together, this work demonstrates the clinical potential of small molecule CXCR4 agonists as novel therapies for pathologic wound healing in diabetes.
Highlights
These compounds were graded according to activity and structure, resulting in 86 compounds that met the criteria as potential CXC chemokine receptor type 4 (CXCR4) agonists for further characterization (Figure 1B)
It is a chemokine that promotes the Secretion of the chemokine Stromal cell-derived factor 1α (SDF-1α), with the subsequent activation of the CXCR4 recruitment of hematopoietic progenitor cells to areas of tissue injury [9,10]
SDF-1α is decreased in diabetic wounds, which may underlie the wound healing impairment promotes the recruitment of hematopoietic progenitor cells to areas of tissue injury [9,10]
Summary
Complications of diabetes, such as impaired wound healing, represent a significant medical problem, with the annual cost of diabetic lower extremity ulcers alone exceeding 1.5 billion dollars [1]. This complex orchestration of wound healing processes is disrupted This impairment is associated with the significantly decreased production of granulation tissue and an increased epithelial gap, compared to non-diabetic wounds [3–7]. In a loss of function experiment, we injected a lentiviral vector that expresses a mutant form of SDF-1α that binds, but does not activate, CXC chemokine receptor type 4 (CXCR4) and measured its effect on granulation tissue formation, angiogenesis, inflammation, cell migration, and wound healing. Screening for small molecule positive modulators that can activate the CXCR4 receptor and its downstream signaling pathway, thereby blocking SDF-1α response, which will provide a novel topical therapy for diabetic wound healing with a reduced risk for systemic receptor activation, and has a great potential for clinical application and commercialization
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