title: Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing.
abstract: Diminished 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.
  
  
  
  Diabetic 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 × 105cells) 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.
  
  
  
  Topical 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.
  
  
  
  We 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.
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, 21936, Republic of Korea.|Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea.
authors.forename: Eunhui
authors.initials: E
authors.lastname: Seo
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, 21936, Republic of Korea.
authors.forename: Jae Soo
authors.initials: JS
authors.lastname: Lim
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, 21936, Republic of Korea.
authors.forename: Jin-Bum
authors.initials: JB
authors.lastname: Jun
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea.|Division of Life Sciences, Korea University, Seoul, 02841, Republic of Korea.
authors.forename: Woohyuk
authors.initials: W
authors.lastname: Choi
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea.
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Hong
authors.affiliation: College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, 21936, Republic of Korea. hsjun@gachon.ac.kr.|Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea. hsjun@gachon.ac.kr.|Gachon Medical Research Institute, Gil Hospital, Incheon, 21565, Republic of Korea. hsjun@gachon.ac.kr.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000473:pathology / Q000628:therapy*; D000077270:Exenatide; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D014688:Venoms; D000077270:Exenatide; D005947:Glucose
keywords: Adipose-derived stem cells; Angiogenesis; Diabetic wound; Exendin-4; GLP-1