Inflammatory Cytokine Induced Regulation of Superoxide Dismutase 3 Expression by Human Mesenchymal Stem Cells

Multiple Sclerosis and Stem Cell Group, Institute of Clinical Neurosciences, Clinical Sciences North Bristol, University of Bristol, Bristol, UK.
Stem cell reviews (Impact Factor: 2.77). 12/2010; 6(4):548-59. DOI: 10.1007/s12015-010-9178-6
Source: PubMed


Increasing evidence suggests that bone marrow derived-mesenchymal stem cells (MSCs) have neuroprotective properties and a major mechanism of action is through their capacity to secrete a diverse range of potentially neurotrophic or anti-oxidant factors. The recent discovery that MSCs secrete superoxide dismutase 3 (SOD3) may help explain studies in which MSCs have a direct anti-oxidant activity that is conducive to neuroprotection in both in vivo and in vitro. SOD3 attenuates tissue damage and reduces inflammation and may confer neuroprotective effects against nitric oxide-mediated stress to cerebellar neurons; but, its role in relation to central nervous system inflammation and neurodegeneration has not been extensively investigated. Here we have performed a series of experiments showing that SOD3 secretion by human bone marrow-derived MSCs is regulated synergistically by the inflammatory cytokines TNF-alpha and IFN-gamma, rather than through direct exposure to reactive oxygen species. Furthermore, we have shown SOD3 secretion by MSCs is increased by activated microglial cells. We have also shown that MSCs and recombinant SOD are able to increase both neuronal and axonal survival in vitro against nitric oxide or microglial induced damage, with an increased MSC-induced neuroprotective effect evident in the presence of inflammatory cytokines TNF-alpha and IFN-gamma. We have shown MSCs are able to convey these neuroprotective effects through secretion of soluble factors alone and furthermore demonstrated that SOD3 secretion by MSCs is, at least, partially responsible for this phenomenon. SOD3 secretion by MSCs maybe of relevance to treatment strategies for inflammatory disease of the central nervous system.

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    • "MSCs can exert direct antioxidant activities through the secretion of antioxidant molecules. They secrete the extracellular antioxidant molecule superoxide dismutase 3 (SOD3)[14,27]. The superoxide dismutase family member SOD3 is the only antioxidant enzyme that scavenges superoxide in the extracellular space and reduces the formation of toxic oxygen and nitrogen products, such as the hydroxyl radical and peroxynitrite. "
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    ABSTRACT: The aim of this study was to examine whether mesenchymal stem cells (MSCs) and/or corneal limbal epithelial stem cells (LSCs) influence restoration of an antioxidant protective mechanism in the corneal epithelium and renewal of corneal optical properties changed after alkali burns. The injured rabbit corneas (with 0.25 N NaOH) were untreated or treated with nanofiber scaffolds free of stem cells, with nanofiber scaffolds seeded with bone marrow MSCs (BM-MSCs), with adipose tissue MSCs (Ad-MSCs), or with LSCs. On day 15 following the injury, after BM-MSCs or LSCs nanofiber treatment (less after Ad-MSCs treatment) the expression of antioxidant enzymes was restored in the regenerated corneal epithelium and the expressions of matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS), α -smooth muscle actin ( α -SMA), transforming growth factor- β 1 (TGF- β 1), and vascular endothelial factor (VEGF) were low. The central corneal thickness (taken as an index of corneal hydration) increased after the injury and returned to levels before the injury. In injured untreated corneas the epithelium was absent and numerous cells revealed the expressions of iNOS, MMP9, α -SMA, TGF- β 1, and VEGF. In conclusion, stem cell treatment accelerated regeneration of the corneal epithelium, restored the antioxidant protective mechanism, and renewed corneal optical properties.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "Studies also showed that use of TNF-α associated with INF-γ promotes increase of HGF, PGE2, and COX-2 levels by MSCs, favoring the inhibition of T-cell proliferation [155]. Furthermore, secretion of superoxide dismutase 3 (SOD3) by human BM-MSCs is regulated synergistically by TNF-α and INF-γ [170]. In turn, SOD3 appears to be involved in the inhibition of T-cell activation and proliferation [171]. "
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    ABSTRACT: Mesenchymal stromal cells (MSCs) are multipotent cells, which can give rise to several cell types including osteoblasts, adipocytes, and chondroblasts. These cells can be found in a variety of adult and fetal tissues, such as bone marrow, adipose tissue, cord blood, and placenta. In recent years, the biological properties of MSCs have attracted the attention of researchers worldwide due to their potential application for treating a series of clinical situations. Among these properties, special attention should be given to the immunoregulatory potential of those cells. MSCs are able to act on all cells of the immune system, which includes the capacity to inhibit the proliferation and function of T-cells. This feature renders them natural candidates to treat several diseases in which cellular immune response is exacerbated. In this review, we outline the main mechanisms by which MSCs immunosuppress T-cell response, focusing on cell-cell contact, secretion of soluble factors, and regulatory T-cell generation. The influence of surface markers in the immunosuppression process and features of MSCs isolated from different sources are also discussed. Finally, the influences of toll-like receptors and cytokines on the inflammatory microenvironment are highlighted regarding the activation of MSCs to exert their immunoregulatory function.
    Full-text · Article · Jun 2014 · BioMed Research International
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    • "Superoxide dismutase [Cu-Zn] 1 and 3 (gene symbols, SOD1 and SOD3) were identified in the present study and found to negatively correlate with neopterin. These results seemed surprising, since SOD3 expression is believed to be up regulated by IFN-γ and TNF-α together [77], while IFN-γ stimulates the production of neopterin. On the other hand, perhaps consistent with the present findings, SOD1 has been reported to be reduced in HIV-infected cognitively impaired patients [78]. "
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