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Mesenchymal Stem Cells Ameliorate Cuprizone-Induced Demyelination by Targeting Oxidative Stress and Mitochondrial Dysfunction

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Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The main causes of MS disease progression, demyelination, and tissue damage are oxidative stress and mitochondrial dysfunction. Hence, the latter are considered as important therapeutic targets. Recent studies have demonstrated that mesenchymal stem cells (MSCs) possess antioxidative properties and are able to target mitochondrial dysfunction. Therefore, we investigated the effect of transplanting Wharton’s jelly-derived MSCs in a demyelination mouse model of MS in which mice were fed cuprizone (CPZ) for 12 weeks. CPZ is a copper chelator that impairs the activity of cytochrome oxidase, decreases oxidative phosphorylation, and produces degenerative changes in oligodendrocytes, leading to toxic demyelination similar to those found in MS patients. Results showed that MSCs caused a significant increase in the percentage of myelinated areas and in the number of myelinated fibers in the corpus callosum of the CPZ + MSC group, compared to the CPZ group, as assessed by Luxol fast blue staining and transmission electron microscopy. In addition, transplantation of MSCs significantly increased the number of oligodendrocytes while decreasing astrogliosis and microgliosis in the corpus callosum of the CPZ + MSC group, evaluated by immunofluorescence. Moreover, the mechanism by which MSCs exert these physiological effects was found to be through abolishing the effect of CPZ on oxidative stress markers and mitochondrial dysfunction. Indeed, malondialdehyde significantly decreased while glutathione and superoxide dismutase significantly increased in CPZ + MSC mice group, in comparison witth the CPZ group alone. Furthermore, cell therapy with MSC transplantation increased the expression levels of mitochondrial biogenesis transcripts PGC1α, NRF1, MFN2, and TFAM. In summary, these results demonstrate that MSCs may attenuate MS by promoting an antioxidant response, reducing oxidative stress, and improving mitochondrial homeostasis.

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Code Availability

In this study, we used imageJ (ImageJ, RRID:SCR_003070) and GraphPad Prism (GraphPad Prism, RRID:SCR_002798) softwares. We also used anti-olig2 (Millipore Cat# AB9610, RRID:AB_570666), anti-GFAP ( Abcam Cat# ab7260, RRID:AB_305808), and anti-Iba1 (Wako Cat# 019–19741, RRID:AB_839504) antibodies.

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Acknowledgements

This study was supported by a grant from Tehran University of Medical Sciences and Health Services, Tehran, Iran (Grant number: 97-03-30-39671), and Lebanese University (2017-25652).

Funding

The current study was supported by a Grant (97-03-30-39671) from the Tehran University of Medical Sciences and Health Services to IRK and a grant from the Lebanese University (2017-25652) to AM.

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Authors and Affiliations

  1. Department of Anatomy, Tehran University of Medical Sciences, Tehran, Iran

    Elham Shiri, Parichehr Pasbakhsh, Maryam Borhani‑Haghighi, Saied Nekoonam, Sina Mojaverrostami & Iraj Ragerdi Kashani

  2. Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran

    Zohreh Alizadeh

  3. Neuroscience Research Center, Vice-Chancellor for Research and Technology, Iran University of Medical Sciences, Tehran, Iran

    Vahid Pirhajati Mahabadi

  4. PRASE and Faculty of Agriculture, Lebanese University, Beirut, Lebanon

    Ali Mehdi

  5. ER045, PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon

    Kazem Zibara

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  1. Elham Shiri
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Correspondence to Kazem Zibara or Iraj Ragerdi Kashani.

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The authors declare that they have no competing financial or non-financial interests.

Ethical Approval

This study was approved by the Ethics Committee (IR.TUMS.MEDICINE.REC.1397.918) of Tehran University of Medical Sciences (Tehran, Iran). Informed consents were signed before collection of human umbilical cords (UC) for isolation of mesenchymal stem cells. The Institutional Animal Care and Use Committee (IACUC) of the Tehran University of Medical Science approved all experiments. Animals were kept in quarantine for approximately 1 week prior to their use. International, national, and institutional guidelines for the care and use of animals were followed. All animals were kept in standard conditions with unlimited access to food and water. Deep anesthesia was employed for animal surgical procedures. Experimental procedures as well as animal housing were carried out in accordance with the European Communities Council Directive (86/609/EEC) and the guidelines of the Iranian Agriculture Ministry.

Consent to Participate

After signing the informed consents, and in order to obtain mesenchymal stem cells, human umbilical cords (UC) were collected from patients undergoing full-term pregnancy and elective for cesarean section.

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Shiri, E., Pasbakhsh, P., Borhani‑Haghighi, M. et al. Mesenchymal Stem Cells Ameliorate Cuprizone-Induced Demyelination by Targeting Oxidative Stress and Mitochondrial Dysfunction. Cell Mol Neurobiol 41, 1467–1481 (2021). https://doi.org/10.1007/s10571-020-00910-6

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