title: Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.
abstract: Although chronic wounds are common, treatment for these disabling conditions remains limited and largely ineffective. In this study, we examined the benefit of bone marrow-derived mesenchymal stem cells (BM-MSCs) in wound healing. Using an excisional wound splinting model, we showed that injection around the wound and application to the wound bed of green fluorescence protein (GFP)(+) allogeneic BM-MSCs significantly enhanced wound healing in normal and diabetic mice compared with that of allogeneic neonatal dermal fibroblasts or vehicle control medium. Fluorescence-activated cell sorting analysis of cells derived from the wound for GFP-expressing BM-MSCs indicated engraftments of 27% at 7 days, 7.6% at 14 days, and 2.5% at 28 days of total BM-MSCs administered. BM-MSC-treated wounds exhibited significantly accelerated wound closure, with increased re-epithelialization, cellularity, and angiogenesis. Notably, BM-MSCs, but not CD34(+) bone marrow cells in the wound, expressed the keratinocyte-specific protein keratin and formed glandular structures, suggesting a direct contribution of BM-MSCs to cutaneous regeneration. Moreover, BM-MSC-conditioned medium promoted endothelial cell tube formation. Real-time polymerase chain reaction and Western blot analysis revealed high levels of vascular endothelial growth factor and angiopoietin-1 in BM-MSCs and significantly greater amounts of the proteins in BM-MSC-treated wounds. Thus, our data suggest that BM-MSCs promote wound healing through differentiation and release of proangiogenic factors. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: 161 HMRC, University of Alberta, 113 Street & 87 Avenue, Edmonton, Alberta T6G 2E1, Canada. yaojiong@ualberta.ca
authors.forename: Yaojiong
authors.initials: Y
authors.lastname: Wu
authors.forename: Liwen
authors.initials: L
authors.lastname: Chen
authors.forename: Paul G
authors.initials: PG
authors.lastname: Scott
authors.forename: Edward E
authors.initials: EE
authors.lastname: Tredget
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000637:transplantation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011897:Random Allocation; D012867:Skin / Q000293:injuries / Q000473:pathology; D014184:Transplantation, Homologous; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000473:pathology / Q000628:therapy*
chemical_list: D042501:Angiogenic Proteins; D049452:Green Fluorescent Proteins; D007633:Keratins