Mesenchymal stem cell‐secreted superoxide dismutase promotes cerebellar neuronal survival

Abstract

It has been postulated that bone marrow-derived mesenchymal stem cells (MSCs) might be effective treatments for neurodegenerative disorders either by replacement of lost cells by differentiation into functional neural tissue; modulation of the immune system to prevent further neurodegeneration; and/or provision of trophic support for the diseased nervous system. Here we have performed a series of experiments showing that human bone marrow-derived MSCs are able to protect cultured rodent cerebellar neurons, and specifically cells expressing Purkinje cell markers, against either nitric oxide exposure or withdrawal of trophic support via cell-cell contact and/or secretion of soluble factors, or through secretion of soluble factors alone. We have demonstrated that MSCs protect cerebellar neurons against toxic insults via modulation of both the phosphatidylinositol 3-kinase/Akt and MAPK pathways and defined superoxide dismutase 3 as a secreted active antioxidant biomolecule by which MSCs modulate, at least in part, their neuroprotective effect on cerebellar cells in vitro. Together, the results demonstrate new and specific mechanisms by which MSCs promote cerebellar neuronal survival and add further evidence to the concept that MSCs may be potential therapeutic agents for neurological disorders involving the cerebellum.

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

“…Importantly, MSCs express CD59, a complement regulatory protein, and also release complement factor H that protects them from complement lysis (Tu et al 2010;Moll et al 2011). In addition, stimulation through C3aR and C5aR protect MSCs from oxidative damage (Schraufstatter et al 2009) and MSCs produce a number of antioxidants including hemeoxygenase-1 and superoxide dismutase (Kemp et al 2010;Mougiakakos et al 2011), and have been shown to suppress oxidative stress and inflammation in ischemia reperfusion injury models in vivo (Chen et al 2011Sun et al 2011;Du et al 2012). The exact mechanisms of action are unclear; however, MSC protection in these models was associated with increased expression of IL-10, heme oxygenase-1 (HO-1), and hepatocyte growth factor, decreased expression of the proinflammatory cytokines IL-1b, TNF-a, and interferon g (IFN-g), reduced reactive oxygen species, reduced apoptosis and decreased numbers of activated T cells, and infiltrating immune cells (Hara et al 2011;Sun et al 2011;Chen et al 2012;Du et al 2012).…”

Cell culture, oxidative stress, and antioxidants: Avoiding pitfalls

“…[73,74] Catalase in the medium can protect against H 2 O 2 generated both intracellularly and extracellularly, since H 2 O 2 readily crosses the cell membranes and so external catalase can "drain" H 2 O 2 out of the cell. [24] Sometimes compounds oxidize in cell culture media but do not generate H 2 O 2 .…”

Current Therapeutic Approaches in Spinal Cord Injury: Pharmacological, Rehabilitation, Cell-based, and Psychological Intervention

“…Another beneficial factor of mesenchymal stem cells is an anti-inflammatory effect. The upregulation of transforming growth factor beta 1, an antiinflammatory factor that controls cell proliferation and apoptosis, has been observed and significantly reduced oxidative stress (Chen et al, 2011;Hawryluk et al, 2012;Kemp et al, 2010;Whone et al, 2012). Unlike others, there are almost no allergic reaction in mesenchymal stem cells.…”