title: Reactive oxygen species induce MMP12-dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord-derived mesenchymal stem cells.
abstract: OBJECTIVE
  Reactive oxygen species (ROS) are potent regulators of stem cell behaviour; however, their physiological significance as regards MMP-mediated regulation of the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) has not been characterized. In the present study, we investigated the role of hydrogen peroxide (H2O2 ) and associated signalling pathways in promoting UCB-MSCs motility.
  
  
  METHODS
  The regulatory effects of H2O2 on the activation of PKC, MAPKs, NF-κB and β-catenin were determined. The expressions of MMP and extracellular matrix proteins were examined. Pharmacological inhibitors and gene-specific siRNA were used to identify the signalling pathways of H2O2 that affect UCB-MSCs motility. An experimental skin wound-healing model was used to confirm the functional role of UCB-MSCs treated with H2O2 in ICR mice.
  
  
  RESULTS
  H2O2 increased the motility of UCB-MSCs by activating PKCα via a calcium influx mechanism. H2O2 activated ERK and p38 MAPK, which are responsible for the distinct activation of transcription factors NF-κB and β-catenin. UCB-MSCs expressed eight MMP genes, but only MMP12 expression was uniquely regulated by NF-κB and β-catenin activation. H2O2 increased the MMP12-dependent degradation of collagen 5 (COL-5) and fibronectin (FN) associated with UCB-MSCs motility. Finally, topical transplantation of UCB-MSCs treated with H2O2 enhanced skin wound healing in mice.
  
  
  CONCLUSIONS
  H2O2 stimulated UCB-MSCs motility by increasing MMP12-dependent degradation of COL-5 and FN through the activation of NF-κB and glycogen synthase kinase-3β/β-catenin, which is critical for providing a suitable microenvironment for MSCs transplantation and re-epithelialization of skin wounds in mice.
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, Korea.
authors.forename: Seung Pil
authors.initials: SP
authors.lastname: Yun
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sang Yub
authors.initials: SY
authors.lastname: Oh
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Jung
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.forename: Han Na
authors.initials: HN
authors.lastname: Suh
authors.forename: Mi Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Keon Bong
authors.initials: KB
authors.lastname: Oh
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D024062:Collagen Type V / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000473:pathology; D014470:Umbilical Cord; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D024062:Collagen Type V; D005353:Fibronectins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051176:beta Catenin; D006861:Hydrogen Peroxide; D053508:Matrix Metalloproteinase 12
keywords: MMP; extracellular matrix proteins; hydrogen peroxide; motility; skin wound healing; umbilical cord blood-derived mesenchymal stem cells