Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

Abstract

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 × 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.

Laser-activated autologous adipose tissue-derived stromal vascular fraction restores spinal cord architecture and function in multiple sclerosis cat model

“…Secondly, MSCs can increase differentiated oligodendrocyte progenitors into mature oligodendrocyte and myelin production as observed by increased immune expression of Olig2 and MPB. This result comes in accordance with [ 94 ]. Thirdly, the potent immunomodulatory, anti-apoptotic, and anti-inflammatory effect of SVF in addition to the secretion of neurotrophic factors that stimulate cell proliferation, promote angiogenesis, inhibit apoptosis, and regulate tissue repair.…”

Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

“…HES1 represses proneural or differentiation genes to keep stem cell progenitors in quiescent or proliferative states ( Ogata et al, 2011 ; Fan et al, 2018 ; Hu and Zou, 2022 ). Importantly, HES1 expression is downregulated during myelination, and HES1 overexpression in OPCs results in impaired oligodendrogenesis ( Li et al, 2021 ). Together, these results show that Ts65Dn trisomy leads to widespread perturbation of TF activity and binding motif accessibility, which may contribute to key elements of trisomy-associated neuropathology.…”

NBP Cytoprotective Effects Promoting Neuronal Differentiation in BMSCs by Inhibiting the p65/Hes1 Pathway

“…The experiments were performed as previously described ( 16 ). The full-length sequence of the p65 gene (NC_051336.1, in the NCBI) and Hes1 gene (NC_051346.1, in the NCBI) was synthesized and subcloned into pcDNA 3.1 vector (GenePharma, Shanghai, P.R.…”