title: Arachidonic acid promotes skin wound healing through induction of human MSC migration by MT3-MMP-mediated fibronectin degradation.
abstract: Arachidonic acid (AA) is largely released during injury, but it has not been fully studied yet how AA modulates wound repair with stem cells. Therefore, we investigated skin wound-healing effect of AA-stimulated human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in vivo and its molecular mechanism in vitro. We found that transplantation of hUCB-MSCs pre-treated with AA enhanced wound filling, re-epithelization, and angiogenesis in a mouse skin excisional wound model. AA significantly promoted hUCB-MSCs migration after a 24 h incubation, which was inhibited by the knockdown of G-protein-coupled receptor 40 (GPR40). AA activated mammalian target of rapamycin complex 2 (mTORC2) and Aktser473 through the GPR40/phosphoinositide 3-kinase (PI3K) signaling, which was responsible for the stimulation of an atypical protein kinase C (PKC) isoform, PKCζ. Subsequently, AA stimulated phosphorylation of p38 MAPK and transcription factor Sp1, and induced membrane type 3-matrix metalloproteinase (MT3-MMP)-dependent fibronectin degradation in promoting hUCB-MSCs motility. Finally, the silencing of MT3-MMP in AA-stimulated hUCB-MSCs failed to promote the repair of skin wounds owing to impaired cell motility. In conclusion, AA enhances skin wound healing through induction of hUCB-MSCs motility by MT3-MMP-mediated fibronectin degradation, which relies on GPR40-dependent mTORC2 signaling pathways.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-741, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Oh
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-741, Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-741, Korea.
authors.forename: Y H
authors.initials: YH
authors.lastname: Jung
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-741, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 151-741, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D053513:Matrix Metalloproteinase 16 / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000090023:Metallothionein 3; D051379:Mice; D008813:Mice, Inbred ICR; D015398:Signal Transduction; D012867:Skin / Q000293:injuries; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D005353:Fibronectins; D000090023:Metallothionein 3; C507104:Mmp16 protein, mouse; C000715430:Mt3 protein, mouse; D016718:Arachidonic Acid; D053513:Matrix Metalloproteinase 16