title: Melatonin enhances the human mesenchymal stem cells motility via melatonin receptor 2 coupling with Gαq in skin wound healing.
abstract: Melatonin, a circadian rhythm-promoting molecule, has a variety of biological functions, but the functional role of melatonin in the motility of mesenchymal stem cells (MSCs) has yet to be studied. In a mouse skin excisional wound model, we found that transplantation of umbilical cord blood (UCB)-MSCs pretreated with melatonin enhanced wound closure, granulation, and re-epithelialization at mouse skin wound sites, where relatively more UCB-MSCs which were engrafted onto the wound site were detected. Thus, we identified the signaling pathway of melatonin, which affects the motility of UCB-MSCs. Melatonin (1 μm) significantly increased the motility of UCB-MSCs, which had been inhibited by the knockdown of melatonin receptor 2 (MT2). We found that Gαq coupled with MT2 and that the binding of Gαq to MT2 uniquely stimulated an atypical PKC isoform, PKCζ. Melatonin induced the phosphorylation of FAK and paxillin, which were concurrently downregulated by blocking of the PKC activity. Melatonin increased the levels of active Cdc42 and Arp2/3, and it has the ability to stimulate cytoskeletal reorganization-related proteins such as profilin-1, cofilin-1, and F-actin in UCB-MSCs. Finally, a lack of MT2 expression in UCB-MSCs during a mouse skin transplantation experiment resulted in impaired wound healing and less engraftment of stem cells at the wound site. These results demonstrate that melatonin signaling via MT2 triggers FAK/paxillin phosphorylation to stimulate reorganization of the actin cytoskeleton, which is responsible for Cdc42/Arp2/3 activation to promote UCB-MSCs motility.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, Korea; BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Jung
authors.forename: Sang Yub
authors.initials: SY
authors.lastname: Oh
authors.forename: Seung Pil
authors.initials: SP
authors.lastname: Yun
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008550:Melatonin / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D018613:Microscopy, Confocal; D044094:Receptors, Melatonin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects; D014162:Transfection; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000975:Antioxidants; D044094:Receptors, Melatonin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D008550:Melatonin
keywords: melatonin; melatonin receptor 2; motility; mouse skin wound; umbilical cord blood-derived mesenchymal stem cells