Cell-Based Reparative Therapies for Multiple Sclerosis

  • Tamir Ben-HurEmail author
  • Nina Fainstein
  • Yossi Nishri
Demyelinating Disorders (DN Bourdette and V Yadav, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Demyelinating Disorders


The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment.


Stem cells Remyelination Immunomodulation Regeneration Cell-based reparative therapies Multiple sclerosis 


Compliance with Ethics Guidelines

Conflict of Interest

Nina Fainstein and Yossi Nishri declare that they have no conflict of interest.

Tamir Ben-Hur has received competitive research grants, as well as grants from private funding sources and donations for basic research. He also has patents regarding the use of human embryonic stem cells, and stock options in Regenera, Pharma and BrainWatch. He has received travel/accommodation expenses covered or reimbursed for invited lectures by academic institutions.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Politis M, Lindvall O. Clinical application of stem cell therapy in Parkinson's disease. BMC Med. 2012;10:1.PubMedCrossRefGoogle Scholar
  2. 2.
    Precious SV, Rosser AE. Producing striatal phenotypes for transplantation in Huntington's disease. Exp Biol Med (Maywood). 2012;237:343–51.CrossRefGoogle Scholar
  3. 3.
    Benraiss A, Goldman SA. Cellular therapy and induced neuronal replacement for Huntington's disease. Neurotherapeutics. 2012;8:577–90.CrossRefGoogle Scholar
  4. 4.
    •• Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell. 2013;12:252–64. With this study, showing extensive migration and myelination by human OPCs in a genetic dysmyelinating mouse model with long-term mouse survival, the stage is set for clinical translation of cell therapy in human dysmyelinating diseases.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang SC, Duncan ID. Remyelination and restoration of axonal function by glial cell transplantation. Prog Brain Res. 2000;127:515–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Blakemore WF, Franklin RJ. Transplantation options for therapeutic central nervous system remyelination. Cell Transplant. 2000;9:289–94.PubMedGoogle Scholar
  7. 7.
    Einstein O, Karussis D, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Abramsky O, et al. Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci. 2003;24:1074–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436:266–71.PubMedCrossRefGoogle Scholar
  9. 9.
    Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol. 2007;61:209–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, et al. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009;66:343–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Aharonowiz M, Einstein O, Fainstein N, Lassmann H, Reubinoff B, Ben-Hur T. Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS One. 2008;3:e3145.PubMedCrossRefGoogle Scholar
  12. 12.
    Papadopoulos D, Pham-Dinh D, Reynolds R. Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat. Exp Neurol. 2006;197:373–85.PubMedCrossRefGoogle Scholar
  13. 13.
    Pluchino S, Zanotti L, Brambilla E, Rovere-Querini P, Capobianco A, Alfaro-Cervello C, et al. Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function. PLoS One. 2009;4:e5959.PubMedCrossRefGoogle Scholar
  14. 14.
    Fainstein N, Vaknin I, Einstein O, Zisman P, Sasson SZ, Baniyash M, et al. Neural precursor cells inhibit multiple inflammatory signals. Mol Cell Neurosci. 2008;39:335–41.PubMedCrossRefGoogle Scholar
  15. 15.
    • Fainstein N, Einstein O, Cohen ME, Brill L, Lavon I, Ben-Hur T. Time limited immunomodulatory functions of transplanted neural precursor cells. Glia. 2013;61:140–9. This is the first study to show limitations in therapeutic plasticity of transplanted stem/precursor cells which restrict their potential in clinical translation. Essentially, transplanted neural precursor cells lose their immunomodulatory properties within several weeks after transplantation.PubMedCrossRefGoogle Scholar
  16. 16.
    Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65:452–6.PubMedCrossRefGoogle Scholar
  17. 17.
    De Feo D, Merlini A, Laterza C, Martino G. Neural stem cell transplantation in central nervous system disorders: from cell replacement to neuroprotection. Curr Opin Neurol. 2012;25:322–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Ruff CA, Wilcox JT, Fehlings MG. Cell-based transplantation strategies to promote plasticity following spinal cord injury. Exp Neurol. 2012;235:78–90.PubMedCrossRefGoogle Scholar
  19. 19.
    Hattiangady B, Shuai B, Cai J, Coksaygan T, Rao MS, Shetty AK. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells. 2007;25:2104–17.PubMedCrossRefGoogle Scholar
  20. 20.
    Ben-Shaanan TL, Ben-Hur T, Yanai J. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Mol Psychiatry. 2008;13:222–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Einstein O, Friedman-Levi Y, Grigoriadis N, Ben-Hur T. Transplanted neural precursors enhance host brain-derived myelin regeneration. J Neurosci. 2009;29:15694–702.PubMedCrossRefGoogle Scholar
  22. 22.
    Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–36.PubMedCrossRefGoogle Scholar
  23. 23.
    Chopp M, Li Y, Zhang J. Plasticity and remodeling of brain. J Neurol Sci. 2008;265:97–101.PubMedCrossRefGoogle Scholar
  24. 24.
    Kassis I, Vaknin-Dembinsky A, Karussis D. Bone marrow mesenchymal stem cells: agents of immunomodulation and neuroprotection. Curr Stem Cell Res Ther. 2011;6:63–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol. 1993;33:137–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Scolding N, Franklin R, Stevens S, Heldin CH, Compston A, Newcombe J. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain. 1998;121:2221–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998;18:601–9.PubMedGoogle Scholar
  29. 29.
    Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci. 2000;20:6404–12.PubMedGoogle Scholar
  30. 30.
    Chang A, Tourtellotte WW, Rudick R, Trapp BD. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002;346:165–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolswijk G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain. 2002;125:338–49.PubMedCrossRefGoogle Scholar
  32. 32.
    Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S, et al. Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Ann Neurol. 2012;72:419–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med. 2005;11:966–72.PubMedGoogle Scholar
  34. 34.
    • Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A. 2010;107:11555–60. This work shows in vitro and in vivo data that provide the molecular basis by which (glial scar derived) hyaluronan inhibits remyelination.PubMedCrossRefGoogle Scholar
  35. 35.
    Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005;8:745–51.PubMedCrossRefGoogle Scholar
  36. 36.
    Charles P, Hernandez MP, Stankoff B, Aigrot MS, Colin C, Rougon G, et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc Natl Acad Sci U S A. 2000;97:7585–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, et al. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Brain. 2002;125:1972–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 2007;13:1228–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Blakemore WF, Irvine KA. Endogenous or exogenous oligodendrocytes for remyelination. J Neurol Sci. 2008;265:43–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain. 2006;129:1972–83.PubMedCrossRefGoogle Scholar
  41. 41.
    Woodruff RH, Franklin RJ. Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study. Glia. 1999;25:216–28.PubMedCrossRefGoogle Scholar
  42. 42.
    Fainstein N, Cohen ME, Ben-Hur T. Time associated decline in neurotrophic properties of neural stem cell grafts render them dependent on brain region-specific environmental support. Neurobiol Dis. 2012;49C:41–8.PubMedGoogle Scholar
  43. 43.
    Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25:4694–705.PubMedCrossRefGoogle Scholar
  44. 44.
    Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci. 2001;21:944–50.PubMedGoogle Scholar
  45. 45.
    Sasaki M, Lankford KL, Radtke C, Honmou O, Kocsis JD. Remyelination after olfactory ensheathing cell transplantation into diverse demyelinating environments. Exp Neurol. 2011;229:88–98.PubMedCrossRefGoogle Scholar
  46. 46.
    Zujovic V, Thibaud J, Bachelin C, Vidal M, Coulpier F, Charnay P, et al. Boundary cap cells are highly competitive for CNS remyelination: fast migration and efficient differentiation in PNS and CNS myelin-forming cells. Stem Cells. 2010;28:470–9.PubMedGoogle Scholar
  47. 47.
    • Bai L, Lennon DP, Caplan AI, DeChant A, Hecker J, Kranso J, et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci. 2012;15:862–70. This study provides the (although probably not the only) molecular basis for the trophic effects of MSCs in EAE. It highlights the important unsolved question of whether treatment with beneficial mediators might be sufficient instead of the need to deliver the entire cell factory for effective therapy.PubMedCrossRefGoogle Scholar
  48. 48.
    Fisher-Shoval Y, Barhum Y, Sadan O, Yust-Katz S, Ben-Zur T, Lev N, et al. Transplantation of placenta-derived mesenchymal stem cells in the EAE mouse model of MS. J Mol Neurosci. 2012;48:176–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Liu R, Zhang Z, Lu Z, Borlongan C, Pan J, Chen J, et al. Human umbilical cord stem cells ameliorate experimental autoimmune encephalomyelitis by regulating immunoinflammation and remyelination. Stem Cells Dev. 2013;22:1053–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Akiyama Y, Radtke C, Kocsis JD. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci. 2002;22:6623–30.PubMedGoogle Scholar
  51. 51.
    Keilhoff G, Stang F, Goihl A, Wolf G, Fansa H. Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol. 2006;26:1235–52.PubMedCrossRefGoogle Scholar
  52. 52.
    Keirstead HS, Ben-Hur T, Rogister B, O'Leary MT, Dubois-Dalcq M, Blakemore WF. Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelinate the CNS after transplantation. J Neurosci. 1999;19:7529–36.PubMedGoogle Scholar
  53. 53.
    Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia. 2003;41:73–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Ben-Hur T, van Heeswijk RB, Einstein O, Aharonowiz M, Xue R, Frost EE, et al. Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice. Magn Reson Med. 2007;57:164–71.PubMedCrossRefGoogle Scholar
  55. 55.
    Muja N, Cohen ME, Zhang J, Kim H, Gilad AA, Walczak P, et al. Neural precursors exhibit distinctly different patterns of cell migration upon transplantation during either the acute or chronic phase of EAE: A serial MR imaging study. Magn Reson Med. 2011;65:1738–49.PubMedCrossRefGoogle Scholar
  56. 56.
    Sadan O, Shemesh N, Barzilay R, Bahat-Stromza M, Melamed E, Cohen Y, et al. Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging. Stem Cells. 2008;26:2542–51.PubMedCrossRefGoogle Scholar
  57. 57.
    Grigoriadis N, Lourbopoulos A, Lagoudaki R, Frischer JM, Polyzoidou E, Touloumi O, et al. Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis. Exp Neurol. 2011;230:78–89.PubMedCrossRefGoogle Scholar
  58. 58.
    Barhum Y, Gai-Castro S, Bahat-Stromza M, Barzilay R, Melamed E, Offen D. Intracerebroventricular transplantation of human mesenchymal stem cells induced to secrete neurotrophic factors attenuates clinical symptoms in a mouse model of multiple sclerosis. J Mol Neurosci. 2010;41:129–37.PubMedCrossRefGoogle Scholar
  59. 59.
    Yang J, Jiang Z, Fitzgerald DC, Ma C, Yu S, Li H, et al. Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. J Clin Invest. 2009;119:3678–91.PubMedCrossRefGoogle Scholar
  60. 60.
    Sher F, Amor S, Gerritsen W, Baker D, Jackson SL, Boddeke E, et al. Intraventricularly injected Olig2-NSCs attenuate established relapsing-remitting EAE in mice. Cell Transplant. 2012;21:1883–97.PubMedCrossRefGoogle Scholar
  61. 61.
    Politi LS, Bacigaluppi M, Brambilla E, Cadioli M, Falini A, Comi G, et al. Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells. 2007;25:2583–92.PubMedCrossRefGoogle Scholar
  62. 62.
    Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95:213–28.PubMedCrossRefGoogle Scholar
  63. 63.
    Payne NL, Sun G, McDonald C, Layton D, Moussa L, Emerson-Webber A, et al. Distinct immunomodulatory and migratory mechanisms underpin the therapeutic potential of human mesenchymal stem cells in autoimmune demyelination. Cell Transplant. 2013;22:1409–25.PubMedCrossRefGoogle Scholar
  64. 64.
    Bulte JW, Ben-Hur T, Miller BR, Mizrachi-Kol R, Einstein O, Reinhartz E, et al. MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain. Magn Reson Med. 2003;50:201–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130:1089–104.PubMedCrossRefGoogle Scholar
  66. 66.
    • Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011;35:986–96. This study suggests the molecular mechanism of transition of MS pathogenesis from a systemic immunologically driven disease to a CNS-compartmentalized disease.PubMedCrossRefGoogle Scholar
  67. 67.
    Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:1187–94.PubMedCrossRefGoogle Scholar
  68. 68.
    Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11:150–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Neurology, The Agnes Ginges Center for Human NeurogeneticsHadassah Hebrew University Medical CenterJerusalemIsrael
  2. 2.Department of NeurologyHadassah University HospitalJerusalemIsrael

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