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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: 3.21). 12/2010; 6(4):548-59. DOI: 10.1007/s12015-010-9178-6
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    • "MSCs harvested from femoral shaft bone marrow were cultured and characterised according to previous published reports from our laboratory [16]–[18], [21], [22]. Briefly, MSC cultures were characterised at third passage using anti-CD105, anti-CD45 (eBioscience, California, USA), anti-CD166 and with anti-CD44 (Serotec, Oxford, UK). "
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