Bone Marrow Mesenchymal Stem Cells Promote Remyelination In Spinal Cord By Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnf Alpha/Relb-Hes1 Pathway: A Rat Model Study Of 2,5-Hexanedione-Induced Neurotoxicity

Background: N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord.Methods: Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 x 10(7) cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD +/- BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNF alpha/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNF alpha was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0.Results: The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNF alpha/RelB signaling. HD was found to increase TNF alpha, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNF alpha to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNF alpha production in OPCs.Conclusions: Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNF alpha/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.