Cell-Based Reparative Therapies for Multiple Sclerosis
- 727 Downloads
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.
KeywordsStem 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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