Reactive oxygen species induce MMP12‐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 (H2O2) and associated signalling pathways in promoting UCB‐MSCs motility. Experimental Approach 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. Key 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 and Implications 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.