Advertisement

Molecular Neurobiology

, Volume 54, Issue 4, pp 2445–2457 | Cite as

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

  • Mansoureh Togha
  • Mehrdad Jahanshahi
  • Leila Alizadeh
  • Soodeh Razeghi Jahromi
  • Gelareh Vakilzadeh
  • Bahram Alipour
  • Ali Gorji
  • Amir Ghaemi
Article

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.

Keywords

Multiple sclerosis Stem cells Neuropharmacology Cytokine Neuroprotection 

Notes

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.

References

  1. 1.
    Graber JJ, McGraw CA, Kimbrough D, Dhib-Jalbut S (2010) Overlapping and distinct mechanisms of action of multiple sclerosis therapies. Clin Neurol Neurosurg 112(7):583–591. doi: 10.1016/j.clineuro.2010.05.002 CrossRefPubMedGoogle Scholar
  2. 2.
    Murray TJ (2009) The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci 277(Suppl 1):S3–8. doi: 10.1016/s0022-510x(09)70003-6 CrossRefPubMedGoogle Scholar
  3. 3.
    Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R, Dijkstra CD, van der Valk P, Bo L (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63(1):16–25. doi: 10.1002/ana.21311 CrossRefPubMedGoogle Scholar
  4. 4.
    Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077. doi: 10.1038/nn.3168 CrossRefPubMedGoogle Scholar
  5. 5.
    Conway D, Cohen JA (2010) Combination therapy in multiple sclerosis. Lancet Neurol 9(3):299–308. doi: 10.1016/s1474-4422(10)70007-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Stuart WH (2007) Combination therapy for the treatment of multiple sclerosis: challenges and opportunities. Curr Med Res Opin 23(6):1199–1208. doi: 10.1185/030079907x187838 CrossRefPubMedGoogle Scholar
  7. 7.
    Fransson M, Piras E, Wang H, Burman J, Duprez I, Harris RA, LeBlanc K, Magnusson PU, Brittebo E, Loskog AS (2014) Intranasal delivery of central nervous system-retargeted human mesenchymal stromal cells prolongs treatment efficacy of experimental autoimmune encephalomyelitis. Immunology 142(3):431–441. doi: 10.1111/imm.12275 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Guo Y, Chan KH, Lai WH, Siu CW, Kwan SC, Tse HF, Wing-Lok Ho P, Wing-Man Ho J (2013) Human mesenchymal stem cells upregulate CD1dCD5(+) regulatory B cells in experimental autoimmune encephalomyelitis. Neuroimmunomodulation 20(5):294–303. doi: 10.1159/000351450 CrossRefPubMedGoogle Scholar
  9. 9.
    Wang X, Kimbrel EA, Ijichi K, Paul D, Lazorchak AS, Chu J, Kouris NA, Yavanian GJ, Lu SJ, Pachter JS, Crocker SJ, Lanza R, Xu RH (2014) Human ESC-derived MSCs outperform bone marrow MSCs in the treatment of an EAE model of multiple sclerosis. Stem Cell Rep 3(1):115–130. doi: 10.1016/j.stemcr.2014.04.020 CrossRefGoogle Scholar
  10. 10.
    Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, Nikbin B, Lotfi J, Khorramnia S, Motamed MR, Togha M, Harirchian MH, Moghadam NB, Alikhani K, Yadegari S, Jafarian S, Gheini MR (2012) Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther 7(6):407–414CrossRefPubMedGoogle Scholar
  11. 11.
    Mirmosayyeb O, Meamar R, Tanhaie AP, Eskandari N, Shaygannejad V (2014) Mesenchymal stem cell therapy in multiple sclerosis: an updated review of the current clinical trials. Multiple Scler Relat Disord 3(6):750. doi: 10.1016/j.msard.2014.09.180 CrossRefGoogle Scholar
  12. 12.
    Rivera FJ, Aigner L (2012) Adult mesenchymal stem cell therapy for myelin repair in multiple sclerosis. Biol Res 45(3):257–268. doi: 10.4067/s0716-97602012000300007 CrossRefPubMedGoogle Scholar
  13. 13.
    Shirian S, Ebrahimi-Barough S, Saberi H, Norouzi-Javidan A, Mousavi SM, Derakhshan MA, Arjmand B, Ai J (2015) Comparison of capability of human bone marrow mesenchymal stem cells and endometrial stem cells to differentiate into motor neurons on electrospun poly(epsilon-caprolactone) scaffold. Molecular neurobiology. doi: 10.1007/s12035-015-9442-5
  14. 14.
    Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD, Miller RH (2009) Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57(11):1192–1203. doi: 10.1002/glia.20841 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F (2006) Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells (Dayton, Ohio) 24(2):386–398. doi: 10.1634/stemcells.2005-0008 CrossRefGoogle Scholar
  16. 16.
    Opitz CA, Litzenburger UM, Lutz C, Lanz TV, Tritschler I, Koppel A, Tolosa E, Hoberg M, Anderl J, Aicher WK, Weller M, Wick W, Platten M (2009) Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. Stem Cells (Dayton, Ohio) 27(4):909–919. doi: 10.1002/stem.7 CrossRefGoogle Scholar
  17. 17.
    Ryan JM, Barry F, Murphy JM, Mahon BP (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149(2):353–363. doi: 10.1111/j.1365-2249.2007.03422.x CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Daoud D, Scheld HH, Speckmann EJ, Gorji A (2007) Rapamycin: brain excitability studied in vitro. Epilepsia 48(4):834–836. doi: 10.1111/j.1528-1167.2006.00976.x CrossRefPubMedGoogle Scholar
  19. 19.
    Saunders RN, Metcalfe MS, Nicholson ML (2001) Rapamycin in transplantation: a review of the evidence. Kidney Int 59(1):3–16. doi: 10.1046/j.1523-1755.2001.00460.x CrossRefPubMedGoogle Scholar
  20. 20.
    Donia M, Mangano K, Amoroso A, Mazzarino MC, Imbesi R, Castrogiovanni P, Coco M, Meroni P, Nicoletti F (2009) Treatment with rapamycin ameliorates clinical and histological signs of protracted relapsing experimental allergic encephalomyelitis in Dark Agouti rats and induces expansion of peripheral CD4 + CD25 + Foxp3+ regulatory T cells. J Autoimmun 33(2):135–140. doi: 10.1016/j.jaut.2009.06.003 CrossRefPubMedGoogle Scholar
  21. 21.
    Esposito M, Ruffini F, Bellone M, Gagliani N, Battaglia M, Martino G, Furlan R (2010) Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation. J Neuroimmunol 220(1-2):52–63. doi: 10.1016/j.jneuroim.2010.01.001 CrossRefPubMedGoogle Scholar
  22. 22.
    Lisi L, Navarra P, Cirocchi R, Sharp A, Stigliano E, Feinstein DL, Dello Russo C (2012) Rapamycin reduces clinical signs and neuropathic pain in a chronic model of experimental autoimmune encephalomyelitis. J Neuroimmunol 243(1-2):43–51. doi: 10.1016/j.jneuroim.2011.12.018 CrossRefPubMedGoogle Scholar
  23. 23.
    Strauss L, Whiteside TL, Knights A, Bergmann C, Knuth A, Zippelius A (2007) Selective survival of naturally occurring human CD4 + CD25 + Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 178(1):320–329CrossRefPubMedGoogle Scholar
  24. 24.
    Girdlestone J, Pido-Lopez J, Srivastava S, Chai J, Leaver N, Galleu A, Lombardi G, Navarrete CV (2015) Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs. Cytotherapy 17(9):1188–1199. doi: 10.1016/j.jcyt.2015.05.009 CrossRefPubMedGoogle Scholar
  25. 25.
    Gharibi B, Farzadi S, Ghuman M, Hughes FJ (2014) Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells (Dayton, Ohio) 32(8):2256–2266. doi: 10.1002/stem.1709 CrossRefGoogle Scholar
  26. 26.
    Kim KW, Moon SJ, Park MJ, Kim BM, Kim EK, Lee SH, Lee EJ, Chung BH, Yang CW, Cho ML (2015) Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease. Stem Cell Res Ther 6:202. doi: 10.1186/s13287-015-0197-8 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Bianco P, Kuznetsov SA, Riminucci M, Gehron Robey P (2006) Postnatal skeletal stem cells. Methods Enzymol 419:117–148. doi: 10.1016/s0076-6879(06)19006-0 CrossRefPubMedGoogle Scholar
  28. 28.
    Jahromi SR, Arrefhosseini SR, Ghaemi A, Alizadeh A, Sabetghadam F, Togha M (2014) Effect of oral genistein administration in early and late phases of allergic encephalomyelitis. Iran J Basic Med Sci 17(7):509–515PubMedPubMedCentralGoogle Scholar
  29. 29.
    Vakilzadeh G, Khodagholi F, Ghadiri T, Darvishi M, Ghaemi A, Noorbakhsh F, Gorji A, Sharifzadeh M (2014) Protective effect of a cAMP analogue on behavioral deficits and neuropathological changes in cuprizone model of demyelination. Molecular neurobiology. doi: 10.1007/s12035-014-8857-8
  30. 30.
    Tahamtan A, Ghaemi A, Gorji A, Kalhor HR, Sajadian A, Tabarraei A, Moradi A, Atyabi F, Kelishadi M (2014) Antitumor effect of therapeutic HPV DNA vaccines with chitosan-based nanodelivery systems. J Biomed Sci 21:69. doi: 10.1186/s12929-014-0069-z CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sajadian A, Tabarraei A, Soleimanjahi H, Fotouhi F, Gorji A, Ghaemi A (2014) Comparing the effect of toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine. Arch Virol 159(8):1951–1960. doi: 10.1007/s00705-014-2024-4 CrossRefPubMedGoogle Scholar
  32. 32.
    Khoury S (2014) Immunology of MS. Multiple Scler Relat Disord 3(6):766. doi: 10.1016/j.msard.2014.09.011 CrossRefGoogle Scholar
  33. 33.
    Paintlia AS, Paintlia MK, Singh I, Skoff RB, Singh AK (2009) Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57(2):182–193. doi: 10.1002/glia.20745 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cruz-Guilloty F, Saeed AM, Duffort S, Cano M, Ebrahimi KB, Ballmick A, Tan Y, Wang H, Laird JM, Salomon RG, Handa JT, Perez VL (2014) T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. PLoS One 9(2):e88201. doi: 10.1371/journal.pone.0088201 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cejka D, Hayer S, Niederreiter B, Sieghart W, Fuereder T, Zwerina J, Schett G (2010) Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum 62(8):2294–2302. doi: 10.1002/art.27504 CrossRefPubMedGoogle Scholar
  36. 36.
    Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E, Roncarolo MG (2006) Induction of tolerance in type 1 diabetes via both CD4 + CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 55(6):1571–1580. doi: 10.2337/db05-1576 CrossRefPubMedGoogle Scholar
  37. 37.
    Iwata H, Nagano T, Toyo-oka K, Hirose H, Hamaoka T, Fujiwara H (1994) Suppression of allograft responses by combining alloantigen-specific i.v. pre-sensitization with suboptimal doses of rapamycin. Int Immunol 6(1):93–99CrossRefPubMedGoogle Scholar
  38. 38.
    Sonobe Y, Jin S, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A (2007) Chronological changes of CD4(+) and CD8(+) T cell subsets in the experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Tohoku J Exp Med 213(4):329–339CrossRefPubMedGoogle Scholar
  39. 39.
    Montero E, Nussbaum G, Kaye JF, Perez R, Lage A, Ben-Nun A, Cohen IR (2004) Regulation of experimental autoimmune encephalomyelitis by CD4+, CD25+ and CD8+ T cells: analysis using depleting antibodies. J Autoimmun 23(1):1–7. doi: 10.1016/j.jaut.2004.05.001 CrossRefPubMedGoogle Scholar
  40. 40.
    Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH (2008) T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 125(2):161–169. doi: 10.1111/j.1365-2567.2008.02837.x CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Huseby ES, Liggitt D, Brabb T, Schnabel B, Ohlen C, Goverman J (2001) A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis. J Exp Med 194(5):669–676CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162(1):1–11. doi: 10.1111/j.1365-2249.2010.04143.x CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Leuenberger T, Paterka M, Reuter E, Herz J, Niesner RA, Radbruch H, Bopp T, Zipp F, Siffrin V (2013) The role of CD8+ T cells and their local interaction with CD4+ T cells in myelin oligodendrocyte glycoprotein35-55-induced experimental autoimmune encephalomyelitis. J Immunol 191(10):4960–4968. doi: 10.4049/jimmunol.1300822 CrossRefPubMedGoogle Scholar
  44. 44.
    Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A (2007) Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61(3):219–227. doi: 10.1002/ana.21076 CrossRefPubMedGoogle Scholar
  45. 45.
    Al Jumah MA, Abumaree MH (2012) The immunomodulatory and neuroprotective effects of mesenchymal stem cells (MSCs) in experimental autoimmune encephalomyelitis (EAE): a model of multiple sclerosis (MS). Int J Mol Sci 13(7):9298–9331. doi: 10.3390/ijms13079298 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T, Chen W, Sun L, Shi S (2012) Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10(5):544–555. doi: 10.1016/j.stem.2012.03.007 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Cheng PP, Liu XC, Ma PF, Gao C, Li JL, Lin YY, Shao W, Han S, Zhao B, Wang LM, Fu JZ, Meng LX, Li Q, Lian QZ, Xia JJ, Qi ZQ (2015) iPSC-MSCs combined with low-dose rapamycin induced islet allograft tolerance through suppressing Th1 and enhancing regulatory T-cell differentiation. Stem Cells Dev 24(15):1793–1804. doi: 10.1089/scd.2014.0488 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ge W, Jiang J, Baroja ML, Arp J, Zassoko R, Liu W, Bartholomew A, Garcia B, Wang H (2009) Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant 9(8):1760–1772. doi: 10.1111/j.1600-6143.2009.02721.x CrossRefPubMedGoogle Scholar
  49. 49.
    Wang H, Qi F, Dai X, Tian W, Liu T, Han H, Zhang B, Li H, Zhang Z, Du C (2014) Requirement of B7-H1 in mesenchymal stem cells for immune tolerance to cardiac allografts in combination therapy with rapamycin. Transpl Immunol 31(2):65–74. doi: 10.1016/j.trim.2014.06.005 CrossRefPubMedGoogle Scholar
  50. 50.
    Hou Y, Ryu CH, Park KY, Kim SM, Jeong CH, Jeun SS (2013) Effective combination of human bone marrow mesenchymal stem cells and minocycline in experimental autoimmune encephalomyelitis mice. Stem Cell Res Ther 4(4):77. doi: 10.1186/scrt228 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Mansoureh Togha
    • 1
  • Mehrdad Jahanshahi
    • 2
  • Leila Alizadeh
    • 3
  • Soodeh Razeghi Jahromi
    • 4
    • 3
  • Gelareh Vakilzadeh
    • 5
  • Bahram Alipour
    • 6
  • Ali Gorji
    • 3
    • 7
  • Amir Ghaemi
    • 8
    • 9
  1. 1.Iranian Center of Neurological Research, Neuroscience Research InstituteTehran University of Medical SciencesTehranIran
  2. 2.Neuroscience Research Center, Department of Anatomy, Faculty of MedicineGolestan University of Medical SciencesGorganIran
  3. 3.Shefa Neuroscience Research CenterTehranIran
  4. 4.Multiple Sclerosis Research Center-Neuroscience Institute, Sina HospitalTehran University of Medical SciencesTehranIran
  5. 5.School of Advanced Technologies in MedicineTehran University of Medical SciencesTehranIran
  6. 6.Iranian Blood Transfusion Organization Research CenterTehranIran
  7. 7.Epilepsy Research Center, Klinik und Poliklinik für Neurochirurgie, Department of NeurologyWestfälische Wilhelms-Universität MünsterMünsterGermany
  8. 8.Infectious Diseases Research Center, Department of MicrobiologyGolestan University of Medical SciencesGorganIran
  9. 9.Department of VirologyInstitute Pasteur of IranTehranIran

Personalised recommendations