Reactive oxygen species induce MMP 12‐dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord‐derived mesenchymal stem cells

Background and Purpose 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 ( H 2 O 2 ) and associated signalling pathways in promoting UCB‐MSCs motility. Experimental Approach The regulatory effects of H 2 O 2 on the activation of PKC , MAPKs , NF ‐κ B 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 H 2 O 2 that affect UCB‐MSCs motility. An experimental skin wound‐healing model was used to confirm the functional role of UCB‐MSCs treated with H 2 O 2 in ICR mice. Key Results H 2 O 2 increased the motility of UCB‐MSCs by activating PKC α via a calcium influx mechanism. H 2 O 2 activated ERK and p 38 MAPK , which are responsible for the distinct activation of transcription factors NF ‐κ B and β‐catenin. UCB ‐ MSCs expressed eight MMP genes, but only MMP 12 expression was uniquely regulated by NF ‐κ B and β‐catenin activation. H 2 O 2 increased the MMP 12‐dependent degradation of collagen 5 ( COL ‐5) and fibronectin ( FN ) associated with UCB‐MSCs motility. Finally, topical transplantation of UCB‐MSCs treated with H 2 O 2 enhanced skin wound healing in mice. Conclusions and Implications H 2 O 2 stimulated UCB‐MSCs motility by increasing MMP 12‐dependent degradation of COL ‐5 and FN through the activation of NF ‐κ B and glycogen synthase kinase‐3β/β‐catenin, which is critical for providing a suitable microenvironment for MSC s transplantation and re‐epithelialization of skin wounds in mice.