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

Background and PurposeReactive 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 ApproachThe 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 ResultsH2O2 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 ImplicationsH2O2 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.

Arachidonic acid promotes skin wound healing through induction of human MSC migration by MT3-MMP-mediated fibronectin degradation

“…In the present study, we found that AA uniquely increases the level of MT3-MMP among all the isoforms of MMP to regulate ECM degradation. In contrast to our previous reports showing that secretory MMP-12 participates in the mobilization of hUCB-MSCs in response to some microenvironmental factors, 14 , 29 we identified that AA exclusively upregulates MT3-MMP through Sp1 in promoting the motility of hUCB-MSCs. This implies that the activation of MMPs is distinctively regulated by microenvironmental factors that affect the transcription of many MMP isotypes.…”

“…As Sp1 is responsible for the transcription of many MMP isotypes, which are crucial for cell migration, 28 mRNA levels of MMP s were analyzed with real-time PCR. Among MMP isotypes expressed in hUCB-MSCs, 29 AA distinctively increased the mRNA levels of MMP-12 and MT3-MMP , and decreased MMP-11 and MT1-MMP ( Figure 6a ). AA also increased the protein expression of MT3-MMP, but did not alter the protein level of MMP-12 ( Figure 6b ).…”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…H 2 O 2 , an important factor that leads to oxidative stress‐induced premature senescence (OSIPS), has been demonstrated to inhibit MSC proliferation in a concentration‐dependent manner . H 2 O 2 enhances the release of NF‐κB and β ‐catenin as well as the motility of MSCs by enhancing degradation of collagen 5 and fibronectin and further facilitates osteogenic differentiation of MSCs via up‐regulation of NFE2L2 expression . After treatment with 200 μm H 2 O 2 for 3 to 4 passages, wharton's Jelly derived MSCs become morphologically heterogeneous and irregularly flattened, with significantly up‐regulated expression of senescence markers, including SA‐ β ‐galactosidase, p53, p21, p16 and lysosomal β ‐galactosidase .…”

Controlling Redox Status for Stem Cell Survival, Expansion, and Differentiation

“…Alternatively, decellularized ECM from MSCs has been shown to promote the resistance against oxidative stress through the secretion of endogenous antioxidants such as SOD2 [ 122 ]. It has been demonstrated that ECM proteins are the targets of ROS through the activation of MMPs, which can affect MSC motility [ 123 ].…”