Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Martino MM, Tortelli F, Mochizuki M, Traub S, Ben-David D, Kuhn GA, et al. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Shen Y, Guo Y, Mikus P, Sulniute R, Wilczynska M, Ny T, et al. Diabetic foot ulcers and their recurrence. Mortality rates and diabetic foot ulcers: is it time to communicate mortality risk to patients with diabetic foot ulceration? J Am Podiatr Med Assoc. Robbins JM, Strauss G, Aron D, Long J, Kuba J, et al. Patients with diabetic foot disease fear major lower-extremity amputation more than death. Diabetes and its negative impact on outcomes in orthopaedic surgery. Stem cells, niches and scaffolds: applications to burns and wound care. Mechanisms of endothelial dysfunction, injury, and death. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1ɑ-VEGF/SDF-1ɑ pathway.
The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. At the molecular level, GDF11 greatly increased HIF-1ɑ expression to enhance the activities of VEGF and SDF-1ɑ, thereby neovascularization. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. Digital images of wound were obtained once a day from D0 to D14 post-wounding. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 μL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db (T2DM) mice. Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood.
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