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Rapamycin Augments Immunomodulatory Properties of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis

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Abstract

The immunomodulatory and anti-inflammatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been considered as an appropriate candidate for treatment of autoimmune diseases. Previous studies have revealed that treatment with BM-MSCs may modulate immune responses and alleviate the symptoms in experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis. Therefore, the present study was designed to examine immunomodulatory effects of BM-MSCs in the treatment of myelin oligodendrocyte glycoprotein (MOG) 35-55-induced EAE in C57BL/6 mice. MSCs were obtained from the bone marrow of C57BL mice, cultured with DMEM/F12, and characterized with flow cytometry for the presence of cell surface markers for BM-MSCs. Following three passages, BM-MSCs were injected intraperitoneally into EAE mice alone or in combination with rapamycin. Immunological and histopathological effects of BM-MSCs and addition of rapamycin to BM-MSCs were evaluated. The results demonstrated that adding rapamycin to BM-MSCs transplantation in EAE mice significantly reduced inflammation infiltration and demyelination, enhanced the immunomodulatory functions, and inhibited progress of neurological impairments compared to BM-MSC transplantation and control groups. The immunological effects of rapamycin and BM-MSC treatments were associated with the inhibition of the Ag-specific lymphocyte proliferation, CD8+ cytolytic activity, and the Th1-type cytokine (gamma-interferon (IFN-γ)) and the increase of Th-2 cytokine (interleukin-4 (IL-4) and IL-10) production. Addition of rapamycin to BM-MSCs was able to ameliorate neurological deficits and provide neuroprotective effects in EAE. This suggests the potential of rapamycin and BM-MSC combined therapy to play neuroprotective roles in the treatment of neuroinflammatory disorders.

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Acknowledgments

This study was supported by Research Deputy at Golestan University of Medical Sciences, Gorgan, Iran and Tehran University of Medical Sciences, Tehran, Iran.

Compliance with Ethical Standards

All the experiments were approved by the Ethical Committee of Golestan University of Medical Sciences, Gorgan, Iran.

Disclosure

All the authors declare that they have no conflict of interests.

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    Authors and Affiliations

    1. Iranian Center of Neurological Research, Neuroscience Research Institute, Tehran University of Medical Sciences, Tehran, Iran

      Mansoureh Togha

    2. Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

      Mehrdad Jahanshahi

    3. Shefa Neuroscience Research Center, Tehran, Iran

      Leila Alizadeh, Soodeh Razeghi Jahromi & Ali Gorji

    4. Multiple Sclerosis Research Center-Neuroscience Institute, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

      Soodeh Razeghi Jahromi

    5. School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

      Gelareh Vakilzadeh

    6. Iranian Blood Transfusion Organization Research Center, Tehran, Iran

      Bahram Alipour

    7. Epilepsy Research Center, Klinik und Poliklinik für Neurochirurgie, Department of Neurology, Westfälische Wilhelms-Universität Münster, Münster, Germany

      Ali Gorji

    8. Infectious Diseases Research Center, Department of Microbiology, Golestan University of Medical Sciences, P.O. Box 49175-1141, Gorgan, Iran

      Amir Ghaemi

    9. Department of Virology, Institute Pasteur of Iran, Tehran, Iran

      Amir Ghaemi

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    Correspondence to Amir Ghaemi.

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    Mansoureh Togha and Mehrdad Jahanshahi contributed equally to this work.

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    Togha, M., Jahanshahi, M., Alizadeh, L. et al. Rapamycin Augments Immunomodulatory Properties of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis. Mol Neurobiol 54, 2445–2457 (2017). https://doi.org/10.1007/s12035-016-9840-3

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