Skip to main content

Advertisement

SpringerLink
Log in

Neural Stem Cell-Based Regenerative Approaches for the Treatment of Multiple Sclerosis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, and demyelinating disorder of the central nervous system (CNS), which ultimately leads to axonal loss and permanent neurological disability. Current treatments for MS are largely comprised of medications that are either immunomodulatory or immunosuppressive and are aimed at reducing the frequency and intensity of relapses. Neural stem cells (NSCs) in the adult brain can differentiate into oligodendrocytes in a context-specific manner and are shown to be involved in the remyelination in these patients. NSCs may exert their beneficial effects not only through oligodendrocyte replacement but also by providing trophic support and immunomodulation, a phenomenon now known as “therapeutic plasticity.” In this review, we first provided an update on the current knowledge regarding MS pathogenesis and the role of immune cells, microglia, and oligodendrocytes in MS disease progression. Next, we reviewed the current progress on research aimed toward stimulating endogenous NSC proliferation and differentiation to oligodendrocytes in vivo and in animal models of demyelination. In addition, we explored the neuroprotective and immunomodulatory effects of transplanted exogenous NSCs on T cell activation, microglial activation, and endogenous remyelination and their effects on the pathological process and prognosis in animal models of MS. Finally, we examined various protocols to generate genetically engineered NSCs as a potential therapy for MS. Overall, this review highlights the studies involving the immunomodulatory, neurotrophic, and regenerative effects of NSCs and novel methods aiming at stimulating the potential of NSCs for the treatment of MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lassmann H (2013) Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci 333(1–2):1–4. doi:10.1016/j.jns.2013.05.010

    Article  CAS  PubMed  Google Scholar 

  2. Kishore A, Kanaujia A, Nag S, Rostami AM, Kenyon LC, Shindler KS, Das Sarma J (2013) Different mechanisms of inflammation induced in virus and autoimmune-mediated models of multiple sclerosis in C57BL6 mice. Biomed Res Int 2013:589048. doi:10.1155/2013/589048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343(20):1430–1438. doi:10.1056/NEJM200011163432001

    Article  CAS  PubMed  Google Scholar 

  4. Miller DH, Leary SM (2007) Primary-progressive multiple sclerosis. Lancet Neurol 6(10):903–912. doi:10.1016/S1474-4422(07)70243-0

    Article  PubMed  Google Scholar 

  5. Fugger L, Friese MA, Bell JI (2009) From genes to function: the next challenge to understanding multiple sclerosis. Nat Rev Immunol 9(6):408–417. doi:10.1038/nri2554

    Article  CAS  PubMed  Google Scholar 

  6. Perga S, Montarolo F, Martire S, Berchialla P, Malucchi S, Bertolotto A (2015) Anti-inflammatory genes associated with multiple sclerosis: a gene expression study. J Neuroimmunol 279:75–78. doi:10.1016/j.jneuroim.2015.01.004

    Article  CAS  PubMed  Google Scholar 

  7. Kohm AP, Carpentier PA, Anger HA, Miller SD (2002) Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169(9):4712–4716

    Article  CAS  PubMed  Google Scholar 

  8. Eliseeva DD, Zavalishin IA, Karaulov AV, Bykovskaia SN (2012) [The role of regulatory T cells in the development of autoimmune process in multiple sclerosis]. Vestnik Rossiiskoi akademii meditsinskikh nauk / Rossiiskaia akademiia meditsinskikh nauk (3):68–74

  9. Peelen E, Damoiseaux J, Smolders J, Knippenberg S, Menheere P, Tervaert JW, Hupperts R, Thewissen M (2011) Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J Neuroimmunol 240-241:97–103. doi:10.1016/j.jneuroim.2011.09.013

    Article  CAS  PubMed  Google Scholar 

  10. Lifshitz GV, Zhdanov DD, Lokhonina AV, Eliseeva DD, Lyssuck EY, Zavalishin IA, Bykovskaia SN (2016) Ex vivo expanded regulatory T cells CD4+CD25+FoxP3+CD127Low develop strong immunosuppressive activity in patients with remitting-relapsing multiple sclerosis. Autoimmunity 49(6):388–396. doi:10.1080/08916934.2016.1199020

    Article  CAS  PubMed  Google Scholar 

  11. Zozulya AL, Wiendl H (2008) The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 4(7):384–398. doi:10.1038/ncpneuro0832

    Article  CAS  PubMed  Google Scholar 

  12. Koch MW, Metz LM, Agrawal SM, Yong VW (2013) Environmental factors and their regulation of immunity in multiple sclerosis. J Neurol Sci 324(1–2):10–16. doi:10.1016/j.jns.2012.10.021

    Article  PubMed  Google Scholar 

  13. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62(1):60–65

    Article  CAS  PubMed  Google Scholar 

  14. Haider L (2015) Inflammation, iron, energy failure, and oxidative stress in the pathogenesis of multiple sclerosis. Oxidative Med Cell Longev 2015:725370. doi:10.1155/2015/725370

    Article  CAS  Google Scholar 

  15. Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schlager C, Lodygin D, Heckelsmiller K, Nietfeld W et al (2012) T cells become licensed in the lung to enter the central nervous system. Nature 488(7413):675–679. doi:10.1038/nature11337

    Article  CAS  PubMed  Google Scholar 

  16. Correale J, Farez MF (2015) Smoking worsens multiple sclerosis prognosis: two different pathways are involved. J Neuroimmunol 281:23–34. doi:10.1016/j.jneuroim.2015.03.006

    Article  CAS  PubMed  Google Scholar 

  17. De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A (2008) Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology 70(13 Pt 2):1113–1118. doi:10.1212/01.wnl.0000294325.63006.f8

    Article  CAS  PubMed  Google Scholar 

  18. Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Bussow K, Sommer N, Hemmer B (2005) Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 115(5):1352–1360. doi:10.1172/JCI23661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Virtanen JO, Farkkila M, Multanen J, Uotila L, Jaaskelainen AJ, Vaheri A, Koskiniemi M (2007) Evidence for human herpesvirus 6 variant A antibodies in multiple sclerosis: diagnostic and therapeutic implications. J Neurovirol 13(4):347–352. doi:10.1080/13550280701381332

    Article  CAS  PubMed  Google Scholar 

  20. Pohl D (2009) Epstein-Barr virus and multiple sclerosis. J Neurol Sci 286(1–2):62–64. doi:10.1016/j.jns.2009.03.028

    Article  CAS  PubMed  Google Scholar 

  21. Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR et al (2014) Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler 20(11):1541–1544. doi:10.1177/1352458514521888

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tsunoda I, Fujinami RS (2002) Inside-out versus outside-in models for virus induced demyelination: axonal damage triggering demyelination. Springer Semin Immunopathol 24(2):105–125. doi:10.1007/s00281-002-0105-z

    Article  CAS  PubMed  Google Scholar 

  23. Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129(2):154–169. doi:10.1111/j.1365-2567.2009.03225.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sato F, Martinez NE, Stewart EC, Omura S, Alexander JS, Tsunoda I (2015) “Microglial nodules” and “newly forming lesions” may be a Janus face of early MS lesions; implications from virus-induced demyelination, the inside-out model. BMC Neurol 15:219. doi:10.1186/s12883-015-0478-y

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hagemeier K, Bruck W, Kuhlmann T (2012) Multiple sclerosis—remyelination failure as a cause of disease progression. Histol Histopathol 27(3):277–287

    CAS  PubMed  Google Scholar 

  26. Stohlman SA, Hinton DR (2001) Viral induced demyelination. Brain Pathol 11(1):92–106

    Article  CAS  PubMed  Google Scholar 

  27. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285. doi:10.1056/NEJM199801293380502

    Article  CAS  PubMed  Google Scholar 

  28. Joshi DC, Zhang CL, Lin TM, Gusain A, Harris MG, Tree E, Yin Y, Wu C et al (2015) Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive. Ms 35(13):5293–5306. doi:10.1523/jneurosci.3859-14.2015

    CAS  Google Scholar 

  29. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269. doi:10.1146/annurev.neuro.30.051606.094313

    Article  CAS  PubMed  Google Scholar 

  30. Birgbauer E, Rao TS, Webb M (2004) Lysolecithin induces demyelination in vitro in a cerebellar slice culture system. J Neurosci Res 78(2):157–166. doi:10.1002/jnr.20248

    Article  CAS  PubMed  Google Scholar 

  31. Andrews H, White K, Thomson C, Edgar J, Bates D, Griffiths I, Turnbull D, Nichols P (2006) Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J Neurosci Res 83(8):1533–1539. doi:10.1002/jnr.20842

    Article  CAS  PubMed  Google Scholar 

  32. Trebst C, Heine S, Lienenklaus S, Lindner M, Baumgartner W, Weiss S, Stangel M (2007) Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination. Acta Neuropathol 114(6):587–596. doi:10.1007/s00401-007-0300-z

    Article  CAS  PubMed  Google Scholar 

  33. Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA et al (2009) Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol 219(2):193–204. doi:10.1002/path.2582

    Article  PubMed  Google Scholar 

  34. Popescu BF, Lucchinetti CF (2012) Pathology of demyelinating diseases. Annu Rev Pathol 7:185–217. doi:10.1146/annurev-pathol-011811-132443

    Article  CAS  PubMed  Google Scholar 

  35. Grade S, Bernardino L, Malva JO (2013) Oligodendrogenesis from neural stem cells: perspectives for remyelinating strategies. Int J Dev Neurosci 31(7):692–700. doi:10.1016/j.ijdevneu.2013.01.004

    Article  CAS  PubMed  Google Scholar 

  36. Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES (1993) Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33(2):137–151. doi:10.1002/ana.410330203

    Article  CAS  PubMed  Google Scholar 

  37. Fancy SP, Zhao C, Franklin RJ (2004) Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. Mol Cell Neurosci 27(3):247–254. doi:10.1016/j.mcn.2004.06.015

    Article  CAS  PubMed  Google Scholar 

  38. Wilson HC, Scolding NJ, Raine CS (2006) Co-expression of PDGF alpha receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions. J Neuroimmunol 176(1–2):162–173. doi:10.1016/j.jneuroim.2006.04.014

    Article  CAS  PubMed  Google Scholar 

  39. Cai J, Qi Y, Hu X, Tan M, Liu Z, Zhang J, Li Q, Sander M et al (2005) Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6 regulation and Shh signaling. Neuron 45(1):41–53. doi:10.1016/j.neuron.2004.12.028

    Article  CAS  PubMed  Google Scholar 

  40. Mecha M, Feliu A, Carrillo-Salinas FJ, Mestre L, Guaza C (2013) Mobilization of progenitors in the subventricular zone to undergo oligodendrogenesis in the Theiler’s virus model of multiple sclerosis: implications for remyelination at lesions sites. Exp Neurol 250:348–352. doi:10.1016/j.expneurol.2013.10.011

    Article  CAS  PubMed  Google Scholar 

  41. Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, Ng SW, Kilpatrick TJ et al (2014) Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci 34(42):14128–14146. doi:10.1523/jneurosci.3491-13.2014

    Article  PubMed  CAS  Google Scholar 

  42. Staugaitis SM, Chang A, Trapp BD (2012) Cortical pathology in multiple sclerosis: experimental approaches to studies on the mechanisms of demyelination and remyelination. Acta Neurol Scand Suppl 195:97–102. doi:10.1111/ane.12041

    Article  Google Scholar 

  43. Dulamea AO (2017) Role of oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol 958:91–127. doi:10.1007/978-3-319-47861-6_7

    Article  PubMed  Google Scholar 

  44. Mason JL, Toews A, Hostettler JD, Morell P, Suzuki K, Goldman JE, Matsushima GK (2004) Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am J Pathol 164(5):1673–1682. doi:10.1016/S0002-9440(10)63726-1

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, Young K, Goncharevich A et al (2010) CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6(6):578–590. doi:10.1016/j.stem.2010.04.002

    Article  CAS  PubMed  Google Scholar 

  46. Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD (2000) NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 20(17):6404–6412

    CAS  PubMed  Google Scholar 

  47. Armstrong RC, Le TQ, Flint NC, Vana AC, Zhou YX (2006) Endogenous cell repair of chronic demyelination. J Neuropathol Exp Neurol 65(3):245–256. doi:10.1097/01.jnen.0000205142.08716.7e

    Article  PubMed  PubMed Central  Google Scholar 

  48. Reynolds R, Dawson M, Papadopoulos D, Polito A, Di Bello IC, Pham-Dinh D, Levine J (2002) The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS. J Neurocytol 31(6–7):523–536

    Article  PubMed  Google Scholar 

  49. Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17(2):210–218. doi:10.1111/j.1750-3639.2007.00064.x

    Article  PubMed  Google Scholar 

  50. Hoftberger R, Aboul-Enein F, Brueck W, Lucchinetti C, Rodriguez M, Schmidbauer M, Jellinger K, Lassmann H (2004) Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol 14(1):43–50

    Article  CAS  PubMed  Google Scholar 

  51. Saxena A, Bauer J, Scheikl T, Zappulla J, Audebert M, Desbois S, Waisman A, Lassmann H et al (2008) Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol 181(3):1617–1621

    Article  CAS  PubMed  Google Scholar 

  52. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55(4):458–468. doi:10.1002/ana.20016

    Article  PubMed  Google Scholar 

  53. McTigue DM, Tripathi RB (2008) The life, death, and replacement of oligodendrocytes in the adult CNS. J Neurochem 107(1):1–19. doi:10.1111/j.1471-4159.2008.05570.x

    Article  CAS  PubMed  Google Scholar 

  54. Thorburne SK, Juurlink BH (1996) Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress. J Neurochem 67(3):1014–1022

    Article  CAS  PubMed  Google Scholar 

  55. Tavazzi E, Rovaris M, La Mantia L (2014) Drug therapy for multiple sclerosis. CMAJ 186(11):833–840. doi:10.1503/cmaj.130727

    Article  PubMed  PubMed Central  Google Scholar 

  56. Weiner HL (2009) The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 65(3):239–248. doi:10.1002/ana.21640

    Article  CAS  PubMed  Google Scholar 

  57. Fitzner D, Simons M (2010) Chronic progressive multiple sclerosis—pathogenesis of neurodegeneration and therapeutic strategies. Curr Neuropharmacol 8(3):305–315. doi:10.2174/157015910792246218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60(1):12–21. doi:10.1002/ana.20913

    Article  CAS  PubMed  Google Scholar 

  59. Stys PK, Zamponi GW, van Minnen J, Geurts JJ (2012) Will the real multiple sclerosis please stand up? Nat Rev Neurosci 13(7):507–514. doi:10.1038/nrn3275

    Article  CAS  PubMed  Google Scholar 

  60. Sato F, Tanaka H, Hasanovic F, Tsunoda I (2011) Theiler’s virus infection: pathophysiology of demyelination and neurodegeneration. Pathophysiology 18(1):31–41. doi:10.1016/j.pathophys.2010.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Oikonen M, Laaksonen M, Aalto V, Ilonen J, Salonen R, Eralinna JP, Panelius M, Salmi A (2011) Temporal relationship between environmental influenza A and Epstein-Barr viral infections and high multiple sclerosis relapse occurrence. Mult Scler 17(6):672–680. doi:10.1177/1352458510394397

    Article  PubMed  Google Scholar 

  62. Procaccini C, De Rosa V, Pucino V, Formisano L, Matarese G (2015) Animal models of multiple sclerosis. Eur J Pharmacol 759:182–191. doi:10.1016/j.ejphar.2015.03.042

    Article  CAS  PubMed  Google Scholar 

  63. von Herrath MG, Fujinami RS, Whitton JL (2003) Microorganisms and autoimmunity: making the barren field fertile? Nat Rev Microbiol 1(2):151–157. doi:10.1038/nrmicro754

    Article  CAS  Google Scholar 

  64. Keough MB, Jensen SK, Yong VW (2015) Experimental demyelination and remyelination of murine spinal cord by focal injection of lysolecithin. J Vis Exp 97. doi:10.3791/52679

  65. Baxi EG, DeBruin J (2015) Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J Neurosci 35(22):8626–8639. doi:10.1523/jneurosci.3817-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA (2014) Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice. Exp Neurol 261:620–632. doi:10.1016/j.expneurol.2014.07.020

    Article  CAS  PubMed  Google Scholar 

  67. Alvarez-Buylla A, Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41(5):683–686

    Article  CAS  PubMed  Google Scholar 

  68. Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G 2nd, Jiang L, Kang J, Nedergaard M et al (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med 9(4):439–447. doi:10.1038/nm837

    Article  CAS  PubMed  Google Scholar 

  69. Luo Y, Coskun V, Liang A, Yu J, Cheng L, Ge W, Shi Z, Zhang K et al (2015) Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell 161(5):1175–1186. doi:10.1016/j.cell.2015.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Andressen C (2013) Neural stem cells: from neurobiology to clinical applications. Curr Pharm Biotechnol 14(1):20–28

    CAS  PubMed  Google Scholar 

  71. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702. doi:10.1016/j.neuron.2011.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Baron-Van Evercooren A (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 11(12):4357–4366

    Article  CAS  PubMed  Google Scholar 

  73. Jablonska A, Kozlowska H, Markiewicz I, Domanska-Janik K, Lukomska B (2010) Transplantation of neural stem cells derived from human cord blood to the brain of adult and neonatal rats. Acta Neurobiol Exp 70(4):337–350

    Google Scholar 

  74. Picard-Riera N, Decker L, Delarasse C, Goude K, Nait-Oumesmar B, Liblau R, Pham-Dinh D, Baron-Van Evercooren A (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A 99(20):13211–13216. doi:10.1073/pnas.192314199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jessberger S, Toni N, Clemenson GD Jr, Ray J, Gage FH (2008) Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat Neurosci 11(8):888–893. doi:10.1038/nn.2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tramontin AD, Garcia-Verdugo JM, Lim DA, Alvarez-Buylla A (2003) Postnatal development of radial glia and the ventricular zone (VZ): a continuum of the neural stem cell compartment. Cereb Cortex 13(6):580–587

    Article  PubMed  Google Scholar 

  77. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26(30):7907–7918. doi:10.1523/JNEUROSCI.1299-06.2006

    Article  CAS  PubMed  Google Scholar 

  78. Capilla-Gonzalez V, Herranz-Perez V, Garcia-Verdugo JM (2015) The aged brain: genesis and fate of residual progenitor cells in the subventricular zone. Front Cell Neurosci 9:365. doi:10.3389/fncel.2015.00365

    Article  PubMed  PubMed Central  Google Scholar 

  79. Conover JC, Shook BA (2011) Aging of the subventricular zone neural stem cell niche. Aging Dis 2(1):49–63

    PubMed  PubMed Central  Google Scholar 

  80. Capilla-Gonzalez V, Cebrian-Silla A, Guerrero-Cazares H, Garcia-Verdugo JM, Quinones-Hinojosa A (2014) Age-related changes in astrocytic and ependymal cells of the subventricular zone. Glia 62(5):790–803. doi:10.1002/glia.22642

    Article  PubMed  PubMed Central  Google Scholar 

  81. Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A et al (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8(5):566–579. doi:10.1016/j.stem.2011.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Samanta J, Grund EM, Silva HM, Lafaille JJ, Fishell G, Salzer JL (2015) Inhibition of Gli1 mobilizes endogenous neural stem cells for remyelination. Nature 526(7573):448–452. doi:10.1038/nature14957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Klingener M, Chavali M, Singh J, McMillan N, Coomes A, Dempsey PJ, Chen EI, Aguirre A (2014) N-cadherin promotes recruitment and migration of neural progenitor cells from the SVZ neural stem cell niche into demyelinated lesions. J Neurosci 34(29):9590–9606. doi:10.1523/JNEUROSCI.3699-13.2014

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Brousse B, Magalon K, Durbec P, Cayre M (2015) Region and dynamic specificities of adult neural stem cells and oligodendrocyte precursors in myelin regeneration in the mouse brain. Biol Open 4(8):980–992. doi:10.1242/bio.012773

    Article  PubMed  PubMed Central  Google Scholar 

  85. Calzolari F, Michel J, Baumgart EV, Theis F, Gotz M, Ninkovic J (2015) Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone. Nat Neurosci 18(4):490–492. doi:10.1038/nn.3963

    Article  CAS  PubMed  Google Scholar 

  86. Lee Y, Oh SB, Park HR, Kim HS, Kim MS, Lee J (2013) Selective impairment on the proliferation of neural progenitor cells by oxidative phosphorylation disruption. Neurosci Lett 535:134–139. doi:10.1016/j.neulet.2012.12.050

    Article  CAS  PubMed  Google Scholar 

  87. Zilkha-Falb R, Kaushansky N, Kawakami N, Ben-Nun A (2016) Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease. J Neuroinflammation 13:7. doi:10.1186/s12974-015-0468-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kaneko N, Kako E, Sawamoto K (2011) Prospects and limitations of using endogenous neural stem cells for brain regeneration. Genes 2(1):107–130. doi:10.3390/genes2010107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shirazi HA, Rasouli J, Ciric B, Rostami A, Zhang GX (2015) 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol 98(2):240–245. doi:10.1016/j.yexmp.2015.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Goudarzvand M, Javan M, Mirnajafi-Zadeh J, Mozafari S, Tiraihi T (2010) Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell Mol Neurobiol 30(2):289–299. doi:10.1007/s10571-009-9451-x

    Article  CAS  PubMed  Google Scholar 

  91. Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106(10):3490–3497. doi:10.1182/blood-2005-05-2044

    Article  CAS  PubMed  Google Scholar 

  92. Toghianifar N, Ashtari F, Zarkesh-Esfahani SH, Mansourian M (2015) Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. J Neuroimmunol 285:125–128. doi:10.1016/j.jneuroim.2015.05.022

    Article  CAS  PubMed  Google Scholar 

  93. Cantarella C, Cayre M, Magalon K, Durbec P (2008) Intranasal HB-EGF administration favors adult SVZ cell mobilization to demyelinated lesions in mouse corpus callosum. Dev Neurobiol 68(2):223–236. doi:10.1002/dneu.20588

    Article  PubMed  Google Scholar 

  94. Holley JE, Gveric D, Newcombe J, Cuzner ML, Gutowski NJ (2003) Astrocyte characterization in the multiple sclerosis glial scar. Neuropathol Appl Neurobiol 29(5):434–444

    Article  CAS  PubMed  Google Scholar 

  95. Amir-Levy Y, Mausner-Fainberg K, Karni A (2014) Treatment with anti-EGF ab ameliorates experimental autoimmune encephalomyelitis via induction of neurogenesis and oligodendrogenesis. Mult Scler Int 2014:926134. doi:10.1155/2014/926134

    PubMed  PubMed Central  Google Scholar 

  96. Cate HS, Sabo JK, Merlo D, Kemper D, Aumann TD, Robinson J, Merson TD, Emery B et al (2010) Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination. J Neurochem 115(1):11–22. doi:10.1111/j.1471-4159.2010.06660.x

    Article  CAS  PubMed  Google Scholar 

  97. Totoiu MO, Nistor GI, Lane TE, Keirstead HS (2004) Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis. Exp Neurol 187(2):254–265. doi:10.1016/j.expneurol.2004.01.028

    Article  CAS  PubMed  Google Scholar 

  98. Hardison JL, Nistor G, Gonzalez R, Keirstead HS, Lane TE (2006) Transplantation of glial-committed progenitor cells into a viral model of multiple sclerosis induces remyelination in the absence of an attenuated inflammatory response. Exp Neurol 197(2):420–429. doi:10.1016/j.expneurol.2005.10.016

    Article  CAS  PubMed  Google Scholar 

  99. Blanc CA, Grist JJ, Rosen H, Sears-Kraxberger I, Steward O, Lane TE (2015) Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. Am J Pathol 185(10):2819–2832. doi:10.1016/j.ajpath.2015.06.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Guan Y, Jiang Z, Ciric B, Rostami AM, Zhang GX (2008) Upregulation of chemokine receptor expression by IL-10/IL-4 in adult neural stem cells. Exp Mol Pathol 85(3):232–236. doi:10.1016/j.yexmp.2008.07.003

    Article  CAS  PubMed  Google Scholar 

  101. Harry GJ, Kraft AD (2012) Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33(2):191–206. doi:10.1016/j.neuro.2012.01.012

    Article  PubMed  PubMed Central  Google Scholar 

  102. Suzumura A (2013) Microglia in pathophysiology of neuroimmunological disorders. Nihon rinsho Jpn J Clin Med 71(5):801–806

    Google Scholar 

  103. van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ et al (2012) Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflammation 9:156. doi:10.1186/1742-2094-9-156

    PubMed  PubMed Central  Google Scholar 

  104. Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201. doi:10.1038/nrneurol.2010.17

    Article  PubMed  Google Scholar 

  105. Al-Shamsi M, Shahin A, Ibrahim MF, Tareq S, Souid AK, Mensah-Brown EP (2015) Bioenergetics of the spinal cord in experimental autoimmune encephalitis of rats. BMC Neurosci 16:37. doi:10.1186/s12868-015-0175-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Lampron A, Larochelle A, Laflamme N, Prefontaine P, Plante MM, Sanchez MG, Yong VW, Stys PK et al (2015) Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 212(4):481–495. doi:10.1084/jem.20141656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ramesh G, Benge S, Pahar B, Philipp MT (2012) A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation 9:72. doi:10.1186/1742-2094-9-72

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141(3):302–313. doi:10.1111/imm.12163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50(5):646–657

    Article  CAS  PubMed  Google Scholar 

  110. Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J (2011) Microglia and neuronal cell death. Neuron Glia Biol 7(1):25–40. doi:10.1017/S1740925X12000014

    Article  PubMed  Google Scholar 

  111. Raivich G, Banati R (2004) Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Brain Res Rev 46(3):261–281. doi:10.1016/j.brainresrev.2004.06.006

    Article  CAS  PubMed  Google Scholar 

  112. Derkow K, Kruger C, Dembny P, Lehnardt S (2015) Microglia induce neurotoxic IL-17+ gammadelta T cells dependent on TLR2, TLR4, and TLR9 activation. PLoS One 10(8):e0135898. doi:10.1371/journal.pone.0135898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Almolda B, Gonzalez B, Castellano B (2015) Are microglial cells the regulators of lymphocyte responses in the CNS? Front Cell Neurosci 9:440. doi:10.3389/fncel.2015.00440

    Article  PubMed  PubMed Central  Google Scholar 

  114. Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T et al (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11(2):146–152. doi:10.1038/nm1177

    Article  CAS  PubMed  Google Scholar 

  115. Zhou J, Cai W, Jin M, Xu J, Wang Y, Xiao Y, Hao L, Wang B et al (2015) 18Beta-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination. Sci Rep 5:13713. doi:10.1038/srep13713

    Article  PubMed  PubMed Central  Google Scholar 

  116. Muja N, Cohen ME, Zhang J, Kim H, Gilad AA, Walczak P, Ben-Hur T, Bulte JW (2011) 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 65(6):1738–1749. doi:10.1002/mrm.22757

    Article  PubMed  PubMed Central  Google Scholar 

  117. Aarum J, Sandberg K, Haeberlein SL, Persson MA (2003) Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A 100(26):15983–15988. doi:10.1073/pnas.2237050100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Cohen ME, Fainstein N, Lavon I, Ben-Hur T (2014) Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis. Stem Cell Res 13(2):227–239. doi:10.1016/j.scr.2014.06.001

    Article  CAS  PubMed  Google Scholar 

  119. Liu J, Hjorth E, Zhu M, Calzarossa C, Samuelsson EB, Schultzberg M, Akesson E (2013) Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model. J Cell Mol Med 17(11):1434–1443. doi:10.1111/jcmm.12123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31(1):149–160. doi:10.1016/j.mcn.2005.10.006

    Article  CAS  PubMed  Google Scholar 

  121. Guadagno J, Xu X, Karajgikar M, Brown A, Cregan SP (2013) Microglia-derived TNFalpha induces apoptosis in neural precursor cells via transcriptional activation of the Bcl-2 family member Puma. Cell Death Dis 4:e538. doi:10.1038/cddis.2013.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu HM, Zhang LF, Ding PS, Liu YJ, Wu X, Zhou JN (2014) Microglial activation mediates host neuronal survival induced by neural stem cells. J Cell Mol Med 18(7):1300–1312. doi:10.1111/jcmm.12281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G et al (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924. doi:10.1038/nn1715

    Article  CAS  PubMed  Google Scholar 

  124. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–657. doi:10.1084/jem.20041611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mosher KI, Andres RH, Fukuhara T, Bieri G, Hasegawa-Moriyama M, He Y, Guzman R, Wyss-Coray T (2012) Neural progenitor cells regulate microglia functions and activity. Nat Neurosci 15(11):1485–1487. doi:10.1038/nn.3233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sakata H, Niizuma K, Yoshioka H, Kim GS, Jung JE, Katsu M, Narasimhan P, Maier CM et al (2012) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32(10):3462–3473. doi:10.1523/jneurosci.5686-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rasmussen S, Imitola J, Ayuso-Sacido A, Wang Y, Starossom SC, Kivisakk P, Zhu B, Meyer M et al (2011) Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol 69(5):878–891. doi:10.1002/ana.22299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Reubinoff BE, Itsykson P, Turetsky T, Pera MF, Reinhartz E, Itzik A, Ben-Hur T (2001) Neural progenitors from human embryonic stem cells. Nat Biotechnol 19(12):1134–1140. doi:10.1038/nbt1201-1134

    Article  CAS  PubMed  Google Scholar 

  129. Nait-Oumesmar B, Picard-Riera N, Kerninon C, Baron-Van Evercooren A (2008) The role of SVZ-derived neural precursors in demyelinating diseases: from animal models to multiple sclerosis. J Neurol Sci 265(1–2):26–31. doi:10.1016/j.jns.2007.09.032

    Article  CAS  PubMed  Google Scholar 

  130. Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO, Maisel M, Lerche H et al (2004) Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 117(Pt 19):4411–4422. doi:10.1242/jcs.01307

    Article  CAS  PubMed  Google Scholar 

  131. Yang J, Yan Y, Ciric B, Yu S, Guan Y, Xu H, Rostami A, Zhang GX (2010) Evaluation of bone marrow- and brain-derived neural stem cells in therapy of central nervous system autoimmunity. Am J Pathol 177(4):1989–2001. doi:10.2353/ajpath.2010.091203

    Article  PubMed  PubMed Central  Google Scholar 

  132. Hew M, O’Connor K, Edel MJ, Lucas M (2015) The possible future roles for iPSC-derived therapy for autoimmune diseases. J Clin Med 4(6):1193–1206. doi:10.3390/jcm4061193

    Article  PubMed  PubMed Central  Google Scholar 

  133. Liu J (2013) Induced pluripotent stem cell-derived neural stem cells: new hope for stroke? Stem Cell Res Ther 4(5):115. doi:10.1186/scrt326

    Article  PubMed  PubMed Central  Google Scholar 

  134. Yan Y, Shin S, Jha BS, Liu Q, Sheng J, Li F, Zhan M, Davis J et al (2013) Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells. Stem Cells Transl Med 2(11):862–870. doi:10.5966/sctm.2013-0080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang T, Choi E, Monaco MC, Campanac E, Medynets M, Do T, Rao P, Johnson KR et al (2013) Derivation of neural stem cells from human adult peripheral CD34+ cells for an autologous model of neuroinflammation. PLoS One 8(11):e81720. doi:10.1371/journal.pone.0081720

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Mozafari S, Laterza C, Roussel D, Bachelin C, Marteyn A, Deboux C, Martino G, Baron-Van Evercooren A (2015) Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice. J Clin Invest 125(9):3642–3656. doi:10.1172/JCI80437

    Article  PubMed  PubMed Central  Google Scholar 

  137. Tao GZ, Lehwald N, Jang KY, Baek J, Xu B, Omary MB, Sylvester KG (2013) Wnt/beta-catenin signaling protects mouse liver against oxidative stress-induced apoptosis through the inhibition of forkhead transcription factor FoxO3. J Biol Chem 288(24):17214–17224. doi:10.1074/jbc.M112.445965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Nicaise AM, Banda E, Guzzo RM, Russomanno K, Castro-Borrero W, Willis CM, Johnson KM, Lo AC et al (2016) iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response. Exp Neurol 288:114–121. doi:10.1016/j.expneurol.2016.11.012

    Article  PubMed  CAS  Google Scholar 

  139. Lee ST, Chu K, Jung KH, Song YM, Jeon D, Kim SU, Kim M, Lee SK et al (2011) Direct generation of neurosphere-like cells from human dermal fibroblasts. PLoS One 6(7):e21801. doi:10.1371/journal.pone.0021801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Capetian P, Azmitia L, Pauly MG, Krajka V, Stengel F, Bernhardi EM, Klett M, Meier B et al (2016) Plasmid-based generation of induced neural stem cells from adult human fibroblasts. Front Cell Neurosci 10:245. doi:10.3389/fncel.2016.00245

    Article  PubMed  PubMed Central  Google Scholar 

  141. Thier M, Worsdorfer P, Lakes YB, Gorris R, Herms S, Opitz T, Seiferling D, Quandel T et al (2012) Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4):473–479. doi:10.1016/j.stem.2012.03.003

    Article  CAS  PubMed  Google Scholar 

  142. Mirakhori F, Zeynali B, Rassouli H, Shahbazi E, Hashemizadeh S, Kiani S, Salekdeh GH, Baharvand H (2015) Induction of neural progenitor-like cells from human fibroblasts via a genetic material-free approach. PLoS One 10(8):e0135479. doi:10.1371/journal.pone.0135479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Miura T, Sugawara T, Fukuda A, Tamoto R, Kawasaki T, Umezawa A, Akutsu H (2015) Generation of primitive neural stem cells from human fibroblasts using a defined set of factors. Biol Open 4(11):1595–1607. doi:10.1242/bio.013151

    Article  PubMed  PubMed Central  Google Scholar 

  144. Lujan E, Chanda S, Ahlenius H, Sudhof TC, Wernig M (2012) Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A 109(7):2527–2532. doi:10.1073/pnas.1121003109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Plaisted WC, Zavala A, Hingco E, Tran H, Coleman R, Lane TE, Loring JF, Walsh CM (2016) Remyelination is correlated with regulatory T cell induction following human embryoid body-derived neural precursor cell transplantation in a viral model of multiple sclerosis. PLoS One 11(6):e0157620. doi:10.1371/journal.pone.0157620

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Hawryluk GW, Mothe AJ, Chamankhah M, Wang J, Tator C, Fehlings MG (2012) In vitro characterization of trophic factor expression in neural precursor cells. Stem Cells Dev 21(3):432–447. doi:10.1089/scd.2011.0242

    Article  CAS  PubMed  Google Scholar 

  147. Fainstein N, Einstein O, Cohen ME, Brill L, Lavon I, Ben-Hur T (2013) Time limited immunomodulatory functions of transplanted neural precursor cells. Glia 61(2):140–149. doi:10.1002/glia.22420

    Article  PubMed  Google Scholar 

  148. Martino G, Franklin RJ, Baron Van Evercooren A, Kerr DA, Stem Cells in Multiple Sclerosis Consensus G (2010) Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol 6(5):247–255. doi:10.1038/nrneurol.2010.35

    Article  PubMed  Google Scholar 

  149. Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, Lavon I, Baniyash M et al (2007) Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 61(3):209–218. doi:10.1002/ana.21033

    Article  CAS  PubMed  Google Scholar 

  150. Pluchino S, Zanotti L, Brambilla E, Rovere-Querini P, Capobianco A, Alfaro-Cervello C, Salani G, Cossetti C et al (2009) Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function. PLoS One 4(6):e5959. doi:10.1371/journal.pone.0005959

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164(4):1079–1106. doi:10.1111/j.1476-5381.2011.01302.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Donega M, Giusto E, Cossetti C, Schaeffer J, Pluchino S (2014) Systemic injection of neural stem/progenitor cells in mice with chronic EAE. J Vis Exp 86. doi:10.3791/51154

  153. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U et al (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422(6933):688–694. doi:10.1038/nature01552

    Article  CAS  PubMed  Google Scholar 

  154. Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O (2003) Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41(1):73–80. doi:10.1002/glia.10159

    Article  PubMed  Google Scholar 

  155. Wu S, Li K, Yan Y, Gran B, Han Y, Zhou F, Guan YT, Rostami A et al (2013) Intranasal delivery of neural stem cells: a CNS-specific, non-invasive cell-based therapy for experimental autoimmune encephalomyelitis. J Clin Cell Immunol 4(3). doi:10.4172/2155-9899.1000142

  156. Guzman R, De Los AA, Cheshier S, Choi R, Hoang S, Liauw J, Schaar B, Steinberg G (2008) Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke 39(4):1300–1306. doi:10.1161/STROKEAHA.107.500470

    Article  PubMed  Google Scholar 

  157. Kokaia Z, Martino G, Schwartz M, Lindvall O (2012) Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci 15(8):1078–1087. doi:10.1038/nn.3163

    Article  CAS  PubMed  Google Scholar 

  158. Martino G, Pluchino S (2006) The therapeutic potential of neural stem cells. Nat Rev Neurosci 7(5):395–406. doi:10.1038/nrn1908

    Article  CAS  PubMed  Google Scholar 

  159. Harris VK, Faroqui R, Vyshkina T, Sadiq SA (2012) Characterization of autologous mesenchymal stem cell-derived neural progenitors as a feasible source of stem cells for central nervous system applications in multiple sclerosis. Stem Cells Transl Med 1(7):536–547. doi:10.5966/sctm.2012-0015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Chen L, Coleman R, Leang R, Tran H, Kopf A, Walsh CM, Sears-Kraxberger I, Steward O et al (2014) Human neural precursor cells promote neurologic recovery in a viral model of multiple sclerosis. Stem Cell Reports 2(6):825–837. doi:10.1016/j.stemcr.2014.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Di Ruscio A, Patti F, Welner RS, Tenen DG, Amabile G (2015) Multiple sclerosis: getting personal with induced pluripotent stem cells. Cell Death Dis 6:e1806. doi:10.1038/cddis.2015.179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Ravanidis S, Poulatsidou KN, Lagoudaki R, Touloumi O, Polyzoidou E, Lourbopoulos A, Nousiopoulou E, Theotokis P et al (2015) Subcutaneous transplantation of neural precursor cells in experimental autoimmune encephalomyelitis reduces chemotactic signals in the central nervous system. Stem Cells Transl Med 4(12):1450–1462. doi:10.5966/sctm.2015-0068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A et al (2005) Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436(7048):266–271. doi:10.1038/nature03889

    Article  CAS  PubMed  Google Scholar 

  164. Einstein O, Karussis D, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Abramsky O, Ben-Hur T (2003) Intraventricular transplantation of neural precursor cell spheres attenuates acute experimental allergic encephalomyelitis. Mol Cell Neurosci 24(4):1074–1082

    Article  CAS  PubMed  Google Scholar 

  165. Whitman LM, Blanc CA, Schaumburg CS, Rowitch DH, Lane TE (2012) Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination. Exp Neurol 235(1):380–387. doi:10.1016/j.expneurol.2012.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Einstein O, Friedman-Levi Y, Grigoriadis N, Ben-Hur T (2009) Transplanted neural precursors enhance host brain-derived myelin regeneration. J Neurosci 29(50):15694–15702. doi:10.1523/JNEUROSCI.3364-09.2009

    Article  CAS  PubMed  Google Scholar 

  167. Harris VK, Yan OJ, Vyshkina T, Sahabi S, Liu X, Sadiq SA (2012) Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci 313(1–2):167–177. doi:10.1016/j.jns.2011.08.036

    Article  PubMed  Google Scholar 

  168. Laterza C, Merlini A, De Feo D, Ruffini F, Menon R, Onorati M, Fredrickx E, Muzio L et al (2013) iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nat Commun 4:2597. doi:10.1038/ncomms3597

    Article  PubMed  CAS  Google Scholar 

  169. Reekmans K, Praet J, De Vocht N, Daans J, Van der Linden A, Berneman Z, Ponsaerts P (2012) Stem cell therapy for multiple sclerosis: preclinical evidence beyond all doubt? Regen Med 7(2):245–259. doi:10.2217/rme.12.5

    Article  CAS  PubMed  Google Scholar 

  170. Ricci-Vitiani L, Lombardi DG, Signore M, Biffoni M, Pallini R, Parati E, Peschle C, De Maria R (2007) Human neural progenitor cells display limited cytotoxicity and increased oligodendrogenesis during inflammation. Cell Death Differ 14(4):876–878. doi:10.1038/sj.cdd.4402078

    Article  CAS  PubMed  Google Scholar 

  171. Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9(11):839–855. doi:10.1038/nrn2480

    Article  CAS  PubMed  Google Scholar 

  172. Walker MR, Patel KK, Stappenbeck TS (2009) The stem cell niche. J Pathol 217(2):169–180. doi:10.1002/path.2474

    Article  CAS  PubMed  Google Scholar 

  173. Ben-Hur T, Ben-Menachem O, Furer V, Einstein O, Mizrachi-Kol R, Grigoriadis N (2003) Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells. Mol Cell Neurosci 24(3):623–631

    Article  CAS  PubMed  Google Scholar 

  174. Foote AK, Blakemore WF (2005) Inflammation stimulates remyelination in areas of chronic demyelination. Brain 128(Pt 3):528–539. doi:10.1093/brain/awh417

    Article  CAS  PubMed  Google Scholar 

  175. Molina-Holgado E, Vela JM, Arevalo-Martin A, Guaza C (2001) LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10. Eur J Neurosci 13(3):493–502

    Article  CAS  PubMed  Google Scholar 

  176. Perez-Asensio FJ, Perpina U, Planas AM, Pozas E (2013) Interleukin-10 regulates progenitor differentiation and modulates neurogenesis in adult brain. J Cell Sci 126(Pt 18):4208–4219. doi:10.1242/jcs.127803

    Article  CAS  PubMed  Google Scholar 

  177. Kulkarni A, Scully TJ, O’Donnell LA (2016) The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation. J Neurosci Res. doi:10.1002/jnr.23987

    PubMed  PubMed Central  Google Scholar 

  178. Kizil C, Kyritsis N, Brand M (2015) Effects of inflammation on stem cells: together they strive? EMBO Rep 16(4):416–426. doi:10.15252/embr.201439702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Liu Q, Sanai N, Jin WN, La Cava A, Van Kaer L, Shi FD (2016) Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci 19(2):243–252. doi:10.1038/nn.4211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Giannakopoulou A, Grigoriadis N, Polyzoidou E, Lourbopoulos A, Michaloudi E, Papadopoulos GC (2011) Time-dependent fate of transplanted neural precursor cells in experimental autoimmune encephalomyelitis mice. Exp Neurol 230(1):16–26. doi:10.1016/j.expneurol.2010.04.011

    Article  PubMed  Google Scholar 

  181. Mueller FJ, Serobyan N, Schraufstatter IU, DiScipio R, Wakeman D, Loring JF, Snyder EY, Khaldoyanidi SK (2006) Adhesive interactions between human neural stem cells and inflamed human vascular endothelium are mediated by integrins. Stem Cells 24(11):2367–2372. doi:10.1634/stemcells.2005-0568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J et al (2004) Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A 101(52):18117–18122. doi:10.1073/pnas.0408258102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Carbajal KS, Schaumburg C, Strieter R, Kane J, Lane TE (2010) Migration of engrafted neural stem cells is mediated by CXCL12 signaling through CXCR4 in a viral model of multiple sclerosis. Proc Natl Acad Sci U S A 107(24):11068–11073. doi:10.1073/pnas.1006375107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R et al (2007) Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci U S A 104(11):4694–4699. doi:10.1073/pnas.0606835104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Abdanipour A, Sagha M, Noori-Zadeh A, Pakzad I, Tiraihi T (2015) In vitro study of the long-term cortisol treatment effects on the growth rate and proliferation of the neural stem/precursor cells. Neurol Res 37(2):117–124. doi:10.1179/1743132814y.0000000431

    Article  CAS  PubMed  Google Scholar 

  186. Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, Porcheri C, Brambilla E et al (2008) Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain 131(Pt 10):2564–2578. doi:10.1093/brain/awn198

    Article  PubMed  PubMed Central  Google Scholar 

  187. Dooley D, Vidal P, Hendrix S (2014) Immunopharmacological intervention for successful neural stem cell therapy: new perspectives in CNS neurogenesis and repair. Pharmacol Ther 141(1):21–31. doi:10.1016/j.pharmthera.2013.08.001

    Article  CAS  PubMed  Google Scholar 

  188. Girard C, Bemelmans AP, Dufour N, Mallet J, Bachelin C, Nait-Oumesmar B, Baron-Van Evercooren A, Lachapelle F (2005) Grafts of brain-derived neurotrophic factor and neurotrophin 3-transduced primate Schwann cells lead to functional recovery of the demyelinated mouse spinal cord. J Neurosci 25(35):7924–7933. doi:10.1523/JNEUROSCI.4890-04.2005

    Article  CAS  PubMed  Google Scholar 

  189. Neri M, Maderna C, Ferrari D, Cavazzin C, Vescovi AL, Gritti A (2010) Robust generation of oligodendrocyte progenitors from human neural stem cells and engraftment in experimental demyelination models in mice. PLoS One 5(4):e10145. doi:10.1371/journal.pone.0010145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Yang J, Yan Y, Xia Y, Kang T, Li X, Ciric B, Xu H, Rostami A et al (2014) Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells. Mol Ther 22(2):440–450. doi:10.1038/mt.2013.241

    Article  CAS  PubMed  Google Scholar 

  191. Gao X, Deng L, Wang Y, Yin L, Yang C, Du J, Yuan Q (2016) GDNF enhances therapeutic efficiency of neural stem cells-based therapy in chronic experimental allergic encephalomyelitis in rat. Stem Cells Int 2016:1431349. doi:10.1155/2016/1431349

    Article  PubMed  PubMed Central  Google Scholar 

  192. Linker RA, Lee DH, Demir S, Wiese S, Kruse N, Siglienti I, Gerhardt E, Neumann H et al (2010) Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis. Brain 133(Pt 8):2248–2263. doi:10.1093/brain/awq179

    Article  PubMed  Google Scholar 

  193. Cao W, Yang Y, Wang Z, Liu A, Fang L, Wu F, Hong J, Shi Y et al (2011) Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity 35(2):273–284. doi:10.1016/j.immuni.2011.06.011

    Article  CAS  PubMed  Google Scholar 

  194. Ma H, Yu B, Kong L, Zhang Y, Shi Y (2012) Neural stem cells over-expressing brain-derived neurotrophic factor (BDNF) stimulate synaptic protein expression and promote functional recovery following transplantation in rat model of traumatic brain injury. Neurochem Res 37(1):69–83. doi:10.1007/s11064-011-0584-1

    Article  CAS  PubMed  Google Scholar 

  195. Chang DJ, Lee N, Choi C, Jeon I, Oh SH, Shin DA, Hwang TS, Lee HJ et al (2013) Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion. Cell Transplant 22(8):1441–1452. doi:10.3727/096368912X657323

    Article  PubMed  Google Scholar 

  196. Kandalam S, Sindji L, Delcroix GJ, Violet F, Garric X, Andre EM, Schiller PC, Venier-Julienne MC (2016) Pharmacologically active microcarriers delivering BDNF within a hydrogel: novel strategy for human bone marrow-derived stem cells neural/neuronal differentiation guidance and therapeutic secretome enhancement. Acta Biomater. doi:10.1016/j.actbio.2016.11.030

    PubMed  Google Scholar 

  197. Klose J, Schmidt NO, Melms A, Dohi M, Miyazaki J, Bischof F, Greve B (2013) Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells. J Neuroinflammation 10:117. doi:10.1186/1742-2094-10-117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Yang J, Jiang Z, Fitzgerald DC, Ma C, Yu S, Li H, Zhao Z, Li Y et al (2009) Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis. J Clin Invest 119(12):3678–3691. doi:10.1172/JCI37914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Gudi V, Skuljec J, Yildiz O, Frichert K, Skripuletz T, Moharregh-Khiabani D, Voss E, Wissel K et al (2011) Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. PLoS One 6(7):e22623. doi:10.1371/journal.pone.0022623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Mason JL, Ye P, Suzuki K, D’Ercole AJ, Matsushima GK (2000) Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci 20(15):5703–5708

    CAS  PubMed  Google Scholar 

  201. Sabo JK, Aumann TD, Kilpatrick TJ, Cate HS (2013) Investigation of sequential growth factor delivery during cuprizone challenge in mice aimed to enhance oligodendrogliogenesis and myelin repair. PLoS One 8(5):e63415. doi:10.1371/journal.pone.0063415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Shi B, Ding J, Liu Y, Zhuang X, Zhuang X, Chen X, Fu C (2014) ERK1/2 pathway-mediated differentiation of IGF-1-transfected spinal cord-derived neural stem cells into oligodendrocytes. PLoS One 9(8):e106038. doi:10.1371/journal.pone.0106038

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Lee YE, An J, Lee KH, Kim SS, Song HJ, Pyeon H, Nam H, Kang K et al (2016) Correction: The synergistic local immunosuppressive effects of neural stem cells expressing Indoleamine 2,3-dioxygenase (IDO) in an experimental autoimmune encephalomyelitis (EAE) animal model. PLoS One 11(2):e0148720. doi:10.1371/journal.pone.0148720

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Sher F, Amor S, Gerritsen W, Baker D, Jackson SL, Boddeke E, Copray S (2012) Intraventricularly injected Olig2-NSCs attenuate established relapsing-remitting EAE in mice. Cell Transplant 21(9):1883–1897. doi:10.3727/096368911X637443

    Article  PubMed  Google Scholar 

  205. Zhou Q, Anderson DJ (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109(1):61–73

    Article  CAS  PubMed  Google Scholar 

  206. Geurts JJ, Bo L, Roosendaal SD, Hazes T, Daniels R, Barkhof F, Witter MP, Huitinga I et al (2007) Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol 66(9):819–827. doi:10.1097/nen.0b013e3181461f54

    Article  PubMed  Google Scholar 

  207. Braun SM, Pilz GA, Machado RA, Moss J, Becher B, Toni N, Jessberger S (2015) Programming hippocampal neural stem/progenitor cells into oligodendrocytes enhances remyelination in the adult brain after injury. Cell Rep 11(11):1679–1685. doi:10.1016/j.celrep.2015.05.024

    Article  CAS  PubMed  Google Scholar 

  208. Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N et al (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci 7(3):221–228. doi:10.1038/nn1188

    Article  CAS  PubMed  Google Scholar 

  209. Li X, Zhang Y, Yan Y, Ciric B, Ma CG, Gran B, Curtis M, Rostami A et al (2016) Neural stem cells engineered to express three therapeutic factors mediate recovery from chronic stage CNS autoimmunity. Mol Ther 24(8):1456–1469. doi:10.1038/mt.2016.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68(1):33–51

    Article  CAS  PubMed  Google Scholar 

  211. Kim SU (2007) Genetically engineered human neural stem cells for brain repair in neurological diseases. Brain Dev 29(4):193–201. doi:10.1016/j.braindev.2006.07.012

    Article  CAS  PubMed  Google Scholar 

  212. Hackett C, Knight J, Mao-Draayer Y (2014) Transplantation of Fas-deficient or wild-type neural stem/progenitor cells (NPCs) is equally efficient in treating experimental autoimmune encephalomyelitis (EAE). Am J Transl Res 6(2):119–128

    PubMed  PubMed Central  Google Scholar 

  213. Glass JD, Hertzberg VS, Boulis NM, Riley J, Federici T, Polak M, Bordeau J, Fournier C et al (2016) Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology 87(4):392–400. doi:10.1212/WNL.0000000000002889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Harris VK, Vyshkina T, Sadiq SA (2016) Clinical safety of intrathecal administration of mesenchymal stromal cell-derived neural progenitors in multiple sclerosis. Cytotherapy 18(12):1476–1482. doi:10.1016/j.jcyt.2016.08.007

    Article  CAS  PubMed  Google Scholar 

  215. Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L et al (2012) Neural stem cell engraftment and myelination in the human brain. Sci Transl Med 4(155):155ra137. doi:10.1126/scitranslmed.3004373

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank the funding support from the National Natural Science Foundation of China (81601373), Hubei Provincial Natural Science Foundation of China (2016CFB407), Bureau of Xiangyang City Science and Technology projects (No.[2014]6-7), Project for Discipline Groups Construction of Food New-type Industrialization of Hubei University of Arts and Science, National Institutes of Health (R01HD087566), National Multiple Sclerosis Society, and Shriners Hospitals for Children.

Author information

Authors and Affiliations

  1. Department of Neurology, Xiang Yang Central Hospital, Medical College of Hubei University of Arts and Science, Xiangyang, Hubei, China

    Juan Xiao, Yunhua Zhu, Xin Qin, Min Zhang, Lihong Zhai, Yi Luo, Xiaoming He & Chun Mao

  2. Department of Biological Treatment, Handan Central Hospital, Handan, Hebei, China

    Juan Xiao & Rongbing Yang

  3. School of Pharmaceutical Sciences, Sun Yat-sen University, Shenzhen, Guangdong, China

    Sangita Biswas & Wenbin Deng

  4. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, 2425 Stockton Boulevard, Sacramento, CA, 95817, USA

    Sangita Biswas & Wenbin Deng

Authors
  1. Juan Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rongbing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sangita Biswas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunhua Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lihong Zhai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoming He
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chun Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wenbin Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided substantial contributions to discussions of the content, and wrote the article.

Corresponding authors

Correspondence to Sangita Biswas or Wenbin Deng.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Additional information

Juan Xiao and Rongbing Yang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, J., Yang, R., Biswas, S. et al. Neural Stem Cell-Based Regenerative Approaches for the Treatment of Multiple Sclerosis. Mol Neurobiol 55, 3152–3171 (2018). https://doi.org/10.1007/s12035-017-0566-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0566-7

Keywords

Search

Navigation