Abstract
BackgroundDiminished wound healing is a major complication of diabetes mellitus and can lead to foot ulcers. However, there are limited therapeutic methods to treat this condition. Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, is known to have many beneficial effects on diabetes. In addition, mesenchymal stem cells are known to have wound healing effects. We investigated the effects of Ex-4 in combination with human adipose tissue-derived stem cells (ADSCs) on diabetic wound healing in a diabetic animal model.MethodsDiabetic db/db (blood glucose levels, >500 mg/dl) or C57BL/6 mice were subjected to wounding on the skin of the back. One day after wounding, each wound received ADSCs (2.5 × 105 cells) injected intradermally around the wound and/or Ex-4 (50 μl of 100 nM Ex-4) topically applied on the wound with a fine brush daily. Wound size was monitored and wound histology was examined. Human endothelial cells and keratinocyte cells were used to assess angiogenesis and vascular endothelial growth factor expression in vitro.ResultsTopical administration of Ex-4 or injection of ADSCs resulted in a rapid reduction of wound size in both diabetic and normoglycemic animals compared with vehicle treatment. Histological analysis also showed rapid skin reconstruction in Ex-4-treated or ADSC-injected wounds. A combination of Ex-4 and ADSCs showed a significantly better therapeutic effect over either treatment alone. In vitro angiogenesis assays showed that both Ex-4 and ADSC-conditioned media (CM) treatment improved migration, invasion and proliferation of human endothelial cells. ADSC-CM also increased migration and proliferation of human keratinocytes. In addition, both Ex-4 and ADSC-CM increased the expression of vascular endothelial growth factor. Co-culture with ADSCs increased migration and proliferation of these cells similar to that found after ADSC-CM treatment.ConclusionsWe suggest that Ex-4 itself is effective for the treatment of diabetic skin wounds, and a combination of topical treatment of Ex-4 and injection of ADSCs has a better therapeutic effect. Thus, a combination of Ex-4 and ADSCs might be an effective therapeutic option for the treatment of diabetic wounds, such as foot ulcers.
Highlights
Diminished wound healing is a major complication of diabetes mellitus and can lead to foot ulcers
Our data show that Ex-4 itself is effective for the treatment of diabetic skin wounds, and a combination of Ex-4 and adipose tissuederived stem cells (ADSCs) showed better therapeutic effects on diabetic wound healing
There were no significant differences between Ex-4 treatment and ADSC transplantation in wound healing rate
Summary
Diminished wound healing is a major complication of diabetes mellitus and can lead to foot ulcers. Mesenchymal stem cells are known to have wound healing effects. We investigated the effects of Ex-4 in combination with human adipose tissuederived stem cells (ADSCs) on diabetic wound healing in a diabetic animal model. Diabetic foot ulcers, which are caused by diminished wound healing, are one of the most serious and costly complications [2, 3] and a major risk factor for lower-limb amputation [4]. New research on advanced therapeutic products such as stem cells, growth factors, skin substitutes, and gene. Seo et al J Transl Med (2017) 15:35 therapy has been conducted. Despite these new therapeutic methods, their efficacy remains poor.
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