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 tr...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-021-02518-z |
| _version_ | 1818365452981633024 |
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| author | Shuangyue Li Huai Guan Yan Zhang Sheng Li Kaixin Li Shuhai Hu Enjun Zuo Cong Zhang Xin Zhang Guanyu Gong Ruoyu Wang Fengyuan Piao |
| author_facet | Shuangyue Li Huai Guan Yan Zhang Sheng Li Kaixin Li Shuhai Hu Enjun Zuo Cong Zhang Xin Zhang Guanyu Gong Ruoyu Wang Fengyuan Piao |
| author_sort | Shuangyue Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T22:20:30Z |
| format | Article |
| id | doaj.art-92fa37cc93ed488ab703e0058ab4e83e |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-13T22:20:30Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-92fa37cc93ed488ab703e0058ab4e83e2022-12-21T23:29:24ZengBMCStem Cell Research & Therapy1757-65122021-08-0112111710.1186/s13287-021-02518-zBone 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 neurotoxicityShuangyue Li0Huai Guan1Yan Zhang2Sheng Li3Kaixin Li4Shuhai Hu5Enjun Zuo6Cong Zhang7Xin Zhang8Guanyu Gong9Ruoyu Wang10Fengyuan Piao11School of Public Health, Dalian Medical UniversityDepartment of Obstetrics and Gynecology, No. 967 Hospital of the Joint Logistics Support Force of the Chinese PLASchool of Public Health, Dalian Medical UniversityDepartment of Biochemistry, Dalian Medical UniversitySchool of Public Health, Dalian Medical UniversityCollege of Stomatology, Dalian Medical UniversityCollege of Stomatology, Dalian Medical UniversitySchool of Public Health, Dalian Medical UniversityDepartment of Clinical Nutrition, The First Affiliated Hospital of Dalian Medical UniversityIntegrative Laboratory, Affiliated Zhongshan Hospital of Dalian UniversityIntegrative Laboratory, Affiliated Zhongshan Hospital of Dalian UniversityIntegrative Laboratory, Affiliated Zhongshan Hospital of Dalian UniversityAbstract 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.https://doi.org/10.1186/s13287-021-02518-zBone marrow-mesenchymal stem cells2,5-HexanedioneDemyelinationRemyelinationOligodendrocyte precursor cellsNotch1 |
| spellingShingle | Shuangyue Li Huai Guan Yan Zhang Sheng Li Kaixin Li Shuhai Hu Enjun Zuo Cong Zhang Xin Zhang Guanyu Gong Ruoyu Wang Fengyuan Piao 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 Stem Cell Research & Therapy Bone marrow-mesenchymal stem cells 2,5-Hexanedione Demyelination Remyelination Oligodendrocyte precursor cells Notch1 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Bone marrow-mesenchymal stem cells 2,5-Hexanedione Demyelination Remyelination Oligodendrocyte precursor cells Notch1 |
| url | https://doi.org/10.1186/s13287-021-02518-z |
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