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.
References
Halliwell, B. (2006). Oxidative stress and neurodegeneration: Where are we now? Journal of Neurochemistry, 97(6), 1634–1658.
Emerit, J., Edeas, M., & Bricaire, F. (2004). Neurodegenerative diseases and oxidative stress. Biomedicine & Pharmacotherapy, 58(1), 39–46.
Lin, M. T., & Beal, M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443(7113), 787–795.
Rosen, D. R. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 364(6435), 362.
Parr, A. M., Tator, C. H., & Keating, A. (2007). Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplantation, 40(7), 609–619.
Wilkins, A., Kemp, K., Ginty, M., Hares, K., Mallam, E., & Scolding, N. (2009). Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res, 3(1), 63–70.
Arnhold, S., Klein, H., Klinz, F. J., et al. (2006). Human bone marrow stroma cells display certain neural characteristics and integrate in the subventricular compartment after injection into the liquor system. European Journal of Cell Biology, 85(6), 551–565.
Hokari, M., Kuroda, S., Shichinohe, H., Yano, S., Hida, K., & Iwasaki, Y. (2008). Bone marrow stromal cells protect and repair damaged neurons through multiple mechanisms. Journal of Neuroscience Research, 86(5), 1024–1035.
Crigler, L., Robey, R. C., Asawachaicharn, A., Gaupp, D., & Phinney, D. G. (2006). Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Experimental Neurology, 198(1), 54–64.
Lanza, C., Morando, S., Voci, A., et al. (2009). Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. Journal of Neurochemistry, 110(5), 1674–1684.
Kemp, K., Hares, K., Mallam, E., Heesom, K. J., Scolding, N., & Wilkins, A. (2009). Mesenchymal stem cell-secreted superoxide dismutase promotes cerebellar neuronal survival. Journal of Neurochemistry, doi:10.1111/j.1471-4159.2009.06553.x.
Ratnam, D. V., Ankola, D. D., Bhardwaj, V., Sahana, D. K., & Kumar, M. N. (2006). Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. Journal of Controlled Release, 113(3), 189–207.
Christofidou-Solomidou, M., & Muzykantov, V. R. (2006). Antioxidant strategies in respiratory medicine. Treatments in Respiratory Medicine, 5(1), 47–78.
Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411), 143–147.
Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317.
Kim, Y. J., Park, H. J., Lee, G., et al. (2009). Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia, 57(1), 13–23.
Broholm, H., Andersen, B., Wanscher, B., et al. (2004). Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurologica Scandinavica, 109(4), 261–269.
Smith, K. J., Kapoor, R., & Felts, P. A. (1999). Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathology, 9(1), 69–92.
Mohamed, A., Shoker, A., Bendjelloul, F., et al. (2003). Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor. Biomedical Sciences Instrumentation, 39, 440–445.
Ruuls, S. R., Van Der Linden, S., Sontrop, K., Huitinga, I., & Dijkstra, C. D. (1996). Aggravation of experimental allergic encephalomyelitis (EAE) by administration of nitric oxide (NO) synthase inhibitors. Clinical and Experimental Immunology, 103(3), 467–474.
Qi, X., Sun, L., Lewin, A. S., Hauswirth, W. W., & Guy, J. (2007). Long-term suppression of neurodegeneration in chronic experimental optic neuritis: Antioxidant gene therapy. Investig Ophthalmol Vis Sci, 48(12), 5360–5370.
Nozik-Grayck, E., Suliman, H. B., & Piantadosi, C. A. (2005). Extracellular superoxide dismutase. The International Journal of Biochemistry & Cell Biology, 37(12), 2466–2471.
Brown, G. C., & Borutaite, V. (2006). Interactions between nitric oxide, oxygen, reactive oxygen species and reactive nitrogen species. Biochemical Society Transactions, 34(Pt 5), 953–956.
Lob, H. E., Marvar, P. J., Guzik, T. J., et al. Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. Hypertension, 55(2), 277–283.
Laurila, J. P., Laatikainen, L. E., Castellone, M. D., & Laukkanen, M. O. (2009). SOD3 reduces inflammatory cell migration by regulating adhesion molecule and cytokine expression. PLoS ONE, 4(6), e5786.
Folz, R. J., Abushamaa, A. M., & Suliman, H. B. (1999). Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia. Journal of Clinical Investigation, 103(7), 1055–1066.
Bowler, R. P., Nicks, M., Tran, K., et al. (2004). Extracellular superoxide dismutase attenuates lipopolysaccharide-induced neutrophilic inflammation. American Journal of Respiratory Cell and Molecular Biology, 31(4), 432–439.
Gao, F., Koenitzer, J. R., Tobolewski, J. M., et al. (2008). Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. The Journal of Biological Chemistry, 283(10), 6058–6066.
Ha, H. Y., Kim, Y., Ryoo, Z. Y., & Kim, T. Y. (2006). Inhibition of the TPA-induced cutaneous inflammation and hyperplasia by EC-SOD. Biochemical and Biophysical Research Communications, 348(2), 450–458.
Lubrano, V., Di Cecco, P., & Zucchelli, G. C. (2006). Role of superoxide dismutase in vascular inflammation and in coronary artery disease. Clinical and Experimental Medicine, 6(2), 84–88.
Rabbani, Z. N., Anscher, M. S., Folz, R. J., et al. (2005). Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity. BMC Cancer, 5(59).
Ueda, J., Starr, M. E., Takahashi, H., et al. (2008). Decreased pulmonary extracellular superoxide dismutase during systemic inflammation. Free Radical Biology & Medicine, 45(6), 897–904.
Marklund, S. L. (1990). Expression of extracellular superoxide dismutase by human cell lines. The Biochemical Journal, 266(1), 213–219.
Harris, C. A., Derbin, K. S., Hunte-McDonough, B., et al. (1991). Manganese superoxide dismutase is induced by IFN-gamma in multiple cell types. Synergistic induction by IFN-gamma and tumor necrosis factor or IL-1. Journal of Immunology, 147(1), 149–154.
Marklund, S. L. (1992). Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. The Journal of Biological Chemistry, 267(10), 6696–6701.
Olofsson, E. M., Marklund, S. L., Pedrosa-Domellof, F., & Behndig, A. (2007). Interleukin-1alpha downregulates extracellular-superoxide dismutase in human corneal keratoconus stromal cells. Molecular Vision, 13, 1285–1290.
Stralin, P., & Marklund, S. L. (2000). Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells. Atherosclerosis, 151(2), 433–441.
Stralin, P., & Marklund, S. L. (2001). Vasoactive factors and growth factors alter vascular smooth muscle cell EC-SOD expression. American Journal of Physiology. Heart and Circulatory Physiology, 281(4), H1621–H1629.
Nathan, C. F., Murray, H. W., Wiebe, M. E., & Rubin, B. Y. (1983). Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. The Journal of Experimental Medicine, 158(3), 670–689.
Berkow, R. L., Wang, D., Larrick, J. W., Dodson, R. W., & Howard, T. H. (1987). Enhancement of neutrophil superoxide production by preincubation with recombinant human tumor necrosis factor. Journal of Immunology, 139(11), 3783–3791.
Matsubara, T., & Ziff, M. (1986). Increased superoxide anion release from human endothelial cells in response to cytokines. Journal of Immunology, 137(10), 3295–3298.
Tiku, M. L., Liesch, J. B., & Robertson, F. M. (1990). Production of hydrogen peroxide by rabbit articular chondrocytes. Enhancement by cytokines. Journal of Immunology, 145(2), 690–696.
Benveniste, E. N., & Benos, D. J. (1995). TNF-alpha- and IFN-gamma-mediated signal transduction pathways: Effects on glial cell gene expression and function. The FASEB Journal, 9(15), 1577–1584.
Shi, N., Kawano, Y., Matsuoka, T., et al. (2009). Increase of CD4 + TNF{alpha} + IL-2-T cells in cerebrospinal fluid of multiple sclerosis patients. Multiple Sclerosis, 15(1), 120–123.
Baraczka, K., Pozsonyi, T., Szuts, I., Ormos, G., & Nekam, K. (2003). Increased levels of tumor necrosis alpha and soluble vascular endothelial adhesion molecule-1 in the cerebrospinal fluid of patients with connective tissue diseases and multiple sclerosis. Acta Microbiologica et Immunologica Hungarica, 50(4), 339–348.
Sharief, M. K., Noori, M. A., Ciardi, M., Cirelli, A., & Thompson, E. J. (1993). Increased levels of circulating ICAM-1 in serum and cerebrospinal fluid of patients with active multiple sclerosis. Correlation with TNF-alpha and blood-brain barrier damage. Journal of Neuroimmunology, 43(1–2), 15–21.
Jensen, M. B., Hegelund, I. V., Lomholt, N. D., Finsen, B., & Owens, T. (2000). IFNgamma enhances microglial reactions to hippocampal axonal degeneration. The Journal of Neuroscience, 20(10), 3612–3621.
Renno, T., Taupin, V., Bourbonniere, L., et al. (1998). Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE. Molecular and Cellular Neurosciences, 12(6), 376–389.
Renno, T., Krakowski, M., Piccirillo, C., Lin, J. Y., & Owens, T. (1995). TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. Journal of Immunology, 154(2), 944–953.
Stralin, P., & Marklund, S. L. (1994). Effects of oxidative stress on expression of extracellular superoxide dismutase, CuZn-superoxide dismutase and Mn-superoxide dismutase in human dermal fibroblasts. Biochemical Journal, 298(Pt 2), 347–352.
Abrams, M. B., Dominguez, C., Pernold, K., et al. (2009). Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restorative Neurology and Neuroscience, 27(4), 307–321.
Park, H. J., Lee, P. H., Ahn, Y. W., et al. (2007). Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. The European Journal of Neuroscience, 26(1), 79–89.
Vercelli, A., Mereuta, O. M., Garbossa, D., et al. (2008). Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiology of Disease, 31(3), 395–405.
Chopp, M., & Li, Y. (2002). Treatment of neural injury with marrow stromal cells. Lancet Neurology, 1(2), 92–100.
Mahmood, A., Lu, D., Lu, M., & Chopp, M. (2003). Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery, 53(3), 697–702. discussion 702–3.
Mahmood, A., Lu, D., Qu, C., Goussev, A., & Chopp, M. (2005). Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery, 57(5), 1026–1031. discussion 1026–31.
Acknowledgements
This work was carried out using a project grant from Ataxia UK.
Disclosures
The authors indicate no potential conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kemp, K., Gray, E., Mallam, E. et al. Inflammatory Cytokine Induced Regulation of Superoxide Dismutase 3 Expression by Human Mesenchymal Stem Cells. Stem Cell Rev and Rep 6, 548–559 (2010). https://doi.org/10.1007/s12015-010-9178-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12015-010-9178-6