Abstract
BackgroundN-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.MethodsSprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 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 TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα 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 TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα 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 TNFα production in OPCs.Conclusions Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.
Highlights
N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material
Our findings demonstrated that Bone marrow mesenchymal stem cells (BMSC) promote remyelination in the spinal cord of HD-exposed rats via Tumor necrosis factor alpha (TNFα)/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease
Quantified data are shown as mean ± Sprague Dawley (SD). a: Compared with control group, p < 0.05; b: compared with HD group, p < 0.05 period), treated with either BMSCs transplantation (HD + BMSCs group, 5 × 107 cells/kg suspended in saline as a bolus dose) or normal saline (HD + Normal saline (NS) group, equal amount of saline used as control) by tail vein injection and observed for another 5 weeks
Summary
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 affect central nervous system. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. Chronic exposure to n-hexane primarily causes sensorimotor polyneuropathy in the peripheral nervous system (PNS), with clinical presentation including muscle wasting, weakness and sensory impairment [2,3,4]. N-hexane/HD neurotoxicity has been suggested to cause segmental demyelination in peripheral nerve fibers [5, 6]. High-dose HD intoxication was found to cause demyelination in PNS and spinal cords and has been used to study the mechanisms of HD neurotoxicity and evaluate the therapeutical potential of various reagents for demyelinating conditions [9]
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