Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing

Journal of Translational Medicine

Research

Jin-Bum Jun¹  Jae Soo Lim¹  Eunhui Seo²  Hee-Sook Jun³  In-Sun Hong⁴  Woohyuk Choi⁵ 

[1] College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 21936, Incheon, Republic of Korea;College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 21936, Incheon, Republic of Korea;Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 21999, Incheon, Republic of Korea;College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 21936, Incheon, Republic of Korea;Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 21999, Incheon, Republic of Korea;Gachon Medical Research Institute, Gil Hospital, 21565, Incheon, Republic of Korea;Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 21999, Incheon, Republic of Korea;Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 21999, Incheon, Republic of Korea;Division of Life Sciences, Korea University, 02841, Seoul, Republic of Korea;

关键词: Diabetic wound;    Angiogenesis;    Exendin-4;    GLP-1;    Adipose-derived stem cells;   

DOI  :  10.1186/s12967-017-1145-4

 received in 2016-11-16, accepted in 2017-02-08,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s) 2017