Endogenous repair and development inspired therapy of neurodegeneration in progressive multiple sclerosis

References

• Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. national multiple sclerosis society (USA) advisory committee on clinical trials of new agents in multiple sclerosis. Neurology. 1996;46:907–911.
   PubMed Web of Science ®Google Scholar
• Imitola J, Chitnis T, Khoury SJ. Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies. Arch Neurol. 2006;63:25–33.
   PubMedGoogle Scholar
• Liu S-Y, Selck C, Friedrich B, et al. Reactivating head regrowth in a regeneration-deficient planarian species. Nature. 2013;500:81–84.
   PubMed Web of Science ®Google Scholar
• Oosterhof N, Boddeke E, van Ham TJ. Immune cell dynamics in the CNS: learning from the zebrafish. Glia. 2015;63:719–735.
   PubMed Web of Science ®Google Scholar
• Parent JM, Elliott RC, Pleasure SJ, et al. Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol. 2006;59:81–91.
   PubMed Web of Science ®Google Scholar
• Encinas JMEA, Michurina TV, Peunova N, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell. 2011;8:566–579.
   PubMed Web of Science ®Google Scholar
• Sanai N, Berger MS, Garcia-Verdugo JM, et al. Comment on “Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension”. Science. 2007;318:393; author reply 393.
   PubMed Web of Science ®Google Scholar
• Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol. 2001;2:762–764.
   PubMed Web of Science ®Google Scholar
• Weiner HL. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008;255(Suppl 1):3–11.
   PubMed Web of Science ®Google Scholar
• Coles AJ, Cox AJ, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253:98–108.
   PubMed Web of Science ®Google Scholar
• Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 2009;8:280–291.
   PubMed Web of Science ®Google Scholar
• Bö L, Dawson TM, Wesselingh S, et al. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol. 1994;36:778–786.
   PubMed Web of Science ®Google Scholar
• Rasmussen S, Wang Y, Kivisäkk P, et al. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing–remitting experimental autoimmune encephalomyelitis. Brain. 2007;130:2816–2829.
   PubMed Web of Science ®Google Scholar
• Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol. 2014;10:225–238.
   PubMed Web of Science ®Google Scholar
• Narayana PA. Magnetic resonance spectroscopy in the monitoring of multiple sclerosis. J Neuroimaging. 2005;15:46s–57s.
   PubMed Web of Science ®Google Scholar
• Li S, Clements R, Sulak M, et al. Decreased NAA in gray matter is correlated with decreased availability of acetate in white matter in postmortem multiple sclerosis cortex. Neurochem Res. 2013;38:2385–2396.
   PubMed Web of Science ®Google Scholar
• Graumann U, Reynolds R, Steck AJ, et al. Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol. 2003;13:554–573.
   PubMed Web of Science ®Google Scholar
• Dutta R, McDonough J, Chang A, et al. Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain. 2007;130:2566–2576.
   PubMed Web of Science ®Google Scholar
• Zeis T, Graumann U, Reynolds R, et al. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain. 2008;131:288–303.
   PubMed Web of Science ®Google Scholar
• Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol. 2011;69:445–454.
   PubMed Web of Science ®Google Scholar
• Albert M, Barrantes-Freer A, Lohrberg M, et al. Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis. Brain Pathol. 2016. doi:10.1111/bpa.12450.
   PubMedGoogle Scholar
• Jürgens T, Jafari M, Kreutzfeldt M, et al. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain. 2016;139:39–46.
   PubMed Web of Science ®Google Scholar
• Mori F, Rossi S, Piccinin S, et al. Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis. J Neurosci. 2013;33:19112–19119.
   PubMed Web of Science ®Google Scholar
• Lindberg RLP, De Groot CJA, Certa U, et al. Multiple sclerosis as a generalized CNS disease–comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J Neuroimmunol. 2004;152:154–167.
   PubMed Web of Science ®Google Scholar
• Galetta KM, Calabresi PA, Frohman EM, et al. Optical coherence tomography (OCT): imaging the visual pathway as a model for neurodegeneration. Neurotherapeutics. 2011;8:117–132.
   PubMed Web of Science ®Google Scholar
• Oksenberg JR. Decoding multiple sclerosis: an update on genomics and future directions. Expert Rev Neurother. 2013;13:11–19.
   PubMed Web of Science ®Google Scholar
• Tallantyre EC, Bø L, Al-Rawashdeh O, et al. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler. 2010;16:406–411.
   PubMed Web of Science ®Google Scholar
• Papadopoulou A, Müller-Lenke N, Naegelin Y, et al. Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis. Mult Scler. 2013;19:1290–1296.
   PubMed Web of Science ®Google Scholar
• Mathey EK, Derfuss T, Storch MK, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med. 2007;204:2363–2372.
   PubMed Web of Science ®Google Scholar
• Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med. 2012;367:115–123.
   PubMed Web of Science ®Google Scholar
• Brill L, Goldberg L, Karni A, et al. Increased anti-KIR4.1 antibodies in multiple sclerosis: could it be a marker of disease relapse? Mult Scler. 2015;21:572–579.
   PubMed Web of Science ®Google Scholar
• Kang Z, Wang C, Zepp J, et al. Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci. 2013;16:1401–1408.
   PubMed Web of Science ®Google Scholar
• Stys PK. White matter injury mechanisms. Curr Mol Med. 2004;4:113–130.
   PubMed Web of Science ®Google Scholar
• Nicot A, Kurnellas M, Elkabes S. Temporal pattern of plasma membrane calcium ATPase 2 expression in the spinal cord correlates with the course of clinical symptoms in two rodent models of autoimmune encephalomyelitis. Eur J Neurosci. 2005;21:2660–2670.
   PubMed Web of Science ®Google Scholar
• Wilkins A, Chandran S, Compston A. A role for oligodendrocyte-derived IGF-1 in trophic support of cortical neurons. Glia. 2001;36:48–57.
   PubMed Web of Science ®Google Scholar
• Genain CP, Cannella B, Hauser SL, et al. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med. 1999;5:170–175.
   PubMed Web of Science ®Google Scholar
• Trotter J. NG2-positive cells in CNS function and the pathological role of antibodies against NG2 in demyelinating diseases. J Neurol Sci. 2005;233:37–42.
   PubMed Web of Science ®Google Scholar
• Teunissen CE, Iacobaeus E, Khademi M, et al. Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology. 2009;72:1322–1329.
   PubMed Web of Science ®Google Scholar
• Trentini A, Comabella M, Tintoré M, et al. N-acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis. J Neurol. 2014;261:2338–2343.
   PubMed Web of Science ®Google Scholar
• Schirmer L, Antel JP, Bruck W, et al. Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis. Brain Pathol. 2011;21:428–440.
   PubMed Web of Science ®Google Scholar
• Gray E, Rice C, Hares K, et al. Reductions in neuronal peroxisomes in multiple sclerosis grey matter. Mult Scler. 2014;20:651–659.
   PubMed Web of Science ®Google Scholar
• Wanders RJ, Waterham HR. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. 2006;75:295–332.
   PubMed Web of Science ®Google Scholar
• Metz I, Traffehn S, Straßburger-Krogias K, et al. Glial cells express nuclear nrf2 after fumarate treatment for multiple sclerosis and psoriasis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e99.
   PubMedGoogle Scholar
• Stevens B, Allen NJ, Vazquez LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–1178.
   PubMed Web of Science ®Google Scholar
• Michailidou I, Willems JGP, Kooi E-J, et al. Complement C1q-C3-associated synaptic changes in multiple sclerosis hippocampus. Ann Neurol. 2015;77:1007–1026.
   PubMed Web of Science ®Google Scholar
• Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–1458.
   PubMed Web of Science ®Google Scholar
• Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–716.
   PubMed Web of Science ®Google Scholar
• Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol. 2014;1:409–422.
   PubMed Web of Science ®Google Scholar
• Ding Z, Mathur V, Ho PP, et al. Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. J Exp Med. 2014;211:189–198.
   PubMed Web of Science ®Google Scholar
• Colombo E, di Dario M, Capitolo E, et al. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014;76:325–337.
   PubMed Web of Science ®Google Scholar
• Warrington AE, Bieber AJ, van Keulen V, et al. Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol. 2004;63:461–473.
   PubMed Web of Science ®Google Scholar
• Wootla B, Denic A, Watzlawik JO, et al. A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis. J Neuroinflammation. 2015;12:83.
   PubMed Web of Science ®Google Scholar
• Watzlawik JO, Warrington AE, Rodriguez M, et al. PDGF is required for remyelinationpromoting IgM stimulation of oligodendrocyte progenitor cell proliferation. Plos One. 2013;8:e55149.
   PubMed Web of Science ®Google Scholar
• Akenami FO, Koskiniemi M, Farkkila M, et al. Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease. J Clin Pathol. 1997;50:157–160.
   PubMed Web of Science ®Google Scholar
• Pelisch N, Dan T, Ichimura A, et al. Plasminogen activator inhibitor-1 antagonist TM5484 attenuatesdemyelination and axonal degeneration in a mice model of multiple sclerosis. Plos One. 2015;10:e0124510.
   Web of Science ®Google Scholar
• Sawcer S, Sawcer S, Hellenthal G, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219.
   PubMed Web of Science ®Google Scholar
• Lassmann H, Van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–656.
   PubMed Web of Science ®Google Scholar
• Imitola J, Co^Té D, Rasmussen S, et al. Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice. J Biomed Opt. 2011;16:021109.
   Web of Science ®Google Scholar
• Goldmann T, Wieghofer P, Müller PF, et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci. 2013;16:1618–1626.
   PubMed Web of Science ®Google Scholar
• Xiao Y, Jin J, Chang M, et al. Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation. Nat Med. 2013;19:595–602.
   PubMed Web of Science ®Google Scholar
• Kotter MR, Zhao C, van Rooijen N, et al. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis. 2005;18:166–175.
   PubMed Web of Science ®Google Scholar
• Miron VE, Boyd A, Zhao J-W, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16:1211–1218.
   PubMed Web of Science ®Google Scholar
• Starossom SC, Mascanfroni ID, Imitola J, et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37:249–263.
   PubMed Web of Science ®Google Scholar
• Mayo L, Trauger SA, Blain M, et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med. 2014;20:1147–1156.
   PubMed Web of Science ®Google Scholar
• Arima Y, Harada M, Kamimura D, et al. Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell. 2012;148:447–457.
   PubMed Web of Science ®Google Scholar
• Shaked I, Hanna RN, Shaked H, et al. Transcription factor Nr4a1 couples sympathetic and inflammatory cues inCNS-recruited macrophages to limit neuroinflammation. Nat Immunol. 2015;16:1228–1234.
   PubMed Web of Science ®Google Scholar
• Fischer MT, Wimmer I, Höftberger R, et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain. 2013;136:1799–1815.
   PubMed Web of Science ®Google Scholar
• Lieury A, Chanal M, Androdias G, et al. Tissue remodeling in periplaque regions of multiple sclerosis spinal cord lesions. Glia. 2014;62:1645–1658.
   PubMed Web of Science ®Google Scholar
• Giannetti P, Politis M, Su P, et al. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study. Neurobiol Dis. 2014;65:203–210.
   PubMed Web of Science ®Google Scholar
• Zhou, J., Cai W, Jin M, et al. 18beta-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination. Sci Rep. 2015;5:13713.
   PubMed Web of Science ®Google Scholar
• Morsali D, Bechtold D, Lee W, et al. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain. 2013;136:1067–1082.
   PubMed Web of Science ®Google Scholar
• Fallarino F, Grohmann U, Vacca C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–1077.
   PubMed Web of Science ®Google Scholar
• Platten M, Ho PP, Youssef S, et al. Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science. 2005;310:850–855.
   PubMed Web of Science ®Google Scholar
• Matsumoto Y, Tsunekawa Y, Nomura T, et al. Differential proliferation rhythm of neural progenitor and oligodendrocyte precursor cells in the young adult hippocampus. Plos One. 2011;6:e27628.
   PubMed Web of Science ®Google Scholar
• Bergles DE, Roberts JD, Somogyi P, et al. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature. 2000;405:187–191.
   PubMed Web of Science ®Google Scholar
• McTigue DM, Tripathi RB. The life, death, and replacement of oligodendrocytes in the adult CNS. J Neurochem. 2008;107:1–19.
   PubMed Web of Science ®Google Scholar
• Dimou L, Simon C, Kirchhoff F, et al. Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci. 2008;28:10434–10442.
   PubMed Web of Science ®Google Scholar
• Gledhill RF, Harrison BM, McDonald WI. Pattern of remyelination in the CNS. Nature. 1973;244:443–444.
   PubMed Web of Science ®Google Scholar
• Clarke LE, Young KM, Hamilton NB, et al. Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J Neurosci. 2012;32:8173–8185.
   PubMed Web of Science ®Google Scholar
• Wolswijk G, Noble M. Identification of an adult-specific glial progenitor cell. Development. 1989;105:387–400.
   PubMed Web of Science ®Google Scholar
• Lucchinetti CF, Popescu BFG, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365:2188–2197.
   PubMed Web of Science ®Google Scholar
• Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–2712.
   PubMed Web of Science ®Google Scholar
• Albert M, Antel J, Brück W, et al. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol. 2007;17:129–138.
   PubMed Web of Science ®Google Scholar
• Seo JH, Maki T, Maeda M, et al. Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling. Plos One. 2014;9:e103174.
   PubMed Web of Science ®Google Scholar
• Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9:540–549.
   PubMed Web of Science ®Google Scholar
• Münzel EJ, Becker CG, Becker T, et al. Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age. Acta Neuropathol Commun. 2014;2:77.
   PubMedGoogle Scholar
• Ruckh JM, Zhao J-W, Shadrach JL, et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell. 2012;10:96–103.
   PubMed Web of Science ®Google Scholar
• Kastriti ME, Sargiannidou I, Kleopa KA, et al. Differential modulation of the juxtaparanodal complex in Multiple Sclerosis. Mol Cell Neurosci. 2015;67:93–103.
   PubMed Web of Science ®Google Scholar
• Markoullis K, Sargiannidou I, Schiza N, et al. Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol. 2012;123:873–886.
   PubMed Web of Science ®Google Scholar
• Pluchino S, Cusimano M, Bacigaluppi M, et al. Remodelling the injured CNS through the establishment of atypical ectopic perivascular neural stem cell niches. Arch Ital Biol. 2010;148:17383.
   Web of Science ®Google Scholar
• Arnett HA, Fancy SPJ, Alberta JA, et al. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science. 2004;306:2111–2115.
   PubMed Web of Science ®Google Scholar
• Wegener A, Deboux C, Bachelin C, et al. Gain of Olig2 function in oligodendrocyte progenitors promotes remyelination. Brain. 2015;138:120–135.
   PubMed Web of Science ®Google Scholar
• Zhu Q, Zhao X, Zheng K, et al. Genetic evidence that Nkx2.2 and Pdgfra are major determinants of the timing of oligodendrocyte differentiation in the developing CNS. Development. 2014;141:548–555.
   PubMed Web of Science ®Google Scholar
• Bujalka, H., et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. Plos Biol. 2013;11:e1001625.
   PubMed Web of Science ®Google Scholar
• Rasmussen S, Imitola J, Ayuso-Sacido A, et al. Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol. 2011;69:878–891.
   PubMed Web of Science ®Google Scholar
• Merkler D, Ernsting T, Kerschensteiner M, et al. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain. 2006;129:1972–1983.
   PubMed Web of Science ®Google Scholar
• Chang A, Tourtellotte WW, Rudick R, et al. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002;346:165–173.
   PubMed Web of Science ®Google Scholar
• Benardais K, Kotsiari A, Skuljec J, et al. Cuprizone [bis(cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox Res. 2013;24:244–250.
   PubMed Web of Science ®Google Scholar
• Mason JL, Toews A, Hostettler JD, et al. Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am J Pathol. 2004;164:1673–1682.
   PubMed Web of Science ®Google Scholar
• Skripuletz T, Hackstette D, Bauer K, et al. Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain. 2013;136:147–167.
   PubMed Web of Science ®Google Scholar
• Lassmann H. Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. Schriftenr Neurol. 1983;25:1–135.
   PubMedGoogle Scholar
• Lucchinetti C, Brück W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707–717.
   PubMed Web of Science ®Google Scholar
• Goldschmidt T, Antel J, Konig FB, et al. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology. 2009;72:1914–1921.
   PubMed Web of Science ®Google Scholar
• Chang A, Smith MC, Yin X, et al. Neurogenesis in the chronic lesions of multiple sclerosis. Brain. 2008;131:2366–2375.
   PubMed Web of Science ®Google Scholar
• Lindner M, Thümmler K, Arthur A, et al. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. Brain. 2015;138:1875–1893.
   PubMed Web of Science ®Google Scholar
• Paintlia AS, Paintlia MK, Singh I, et al. Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis. Exp Neurol. 2008;214:168–180.
   PubMed Web of Science ®Google Scholar
• Frischer JM, Bramow S, Dal-Bianco A, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175–1189.
   PubMed Web of Science ®Google Scholar
• Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74:1033–1040.
   PubMed Web of Science ®Google Scholar
• Sun X, Liu Y, Liu B, et al. Rolipram promotes remyelination possibly via MEK-ERK signal pathway in cuprizone-induced demyelination mouse. Exp Neurol. 2012;237:304–311.
   PubMed Web of Science ®Google Scholar
• Ravni A, Vaudry D, Gerdin MJ, et al. A cAMP-dependent, protein kinase A-independent signaling pathway mediating neuritogenesis through Egr1 in PC12 cells. Mol Pharmacol. 2008;73:1688–1708.
   PubMed Web of Science ®Google Scholar
• Fyffe-Maricich SL, Karlo JC, Landreth GE, et al. The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. J Neurosci. 2011;31:843–850.
   PubMed Web of Science ®Google Scholar
• Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015;73:254–268.
   PubMed Web of Science ®Google Scholar
• Mei F, Fancy SPJ, Shen Y-A-A, et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014;20:954–960.
   PubMed Web of Science ®Google Scholar
• Najm FJ, Madhavan M, Zaremba A, et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature. 2015;522:216–220.
   PubMed Web of Science ®Google Scholar
• Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7:221–228.
   PubMed Web of Science ®Google Scholar
• Mi S, Miller RH, Lee X, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005;8:745–751.
   PubMed Web of Science ®Google Scholar
• Wang C-J, Qu C-Q, Zhang J, et al. Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis. Anat Rec (Hoboken). 2014;297:2356–2363.
   PubMedGoogle Scholar
• Tran JQ, Rana J, Barkhof F, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014;1:e18.
   PubMedGoogle Scholar
• Doetsch F. The glial identity of neural stem cells. Nat Neurosci. 2003;6:1127–1134.
   PubMed Web of Science ®Google Scholar
• Guo F, Maeda Y, Ma J, et al. Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J Neurosci. 2010;30:12036–12049.
   PubMed Web of Science ®Google Scholar
• Lin S-C, Bergles DE. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nat Neurosci. 2004;7:24–32.
   PubMed Web of Science ®Google Scholar
• Imitola J, Raddassi K, Park KI, et al. 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. 2004;101:18117–18122.
   PubMed Web of Science ®Google Scholar
• Lu M, Grove EA, Miller RJ. Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A. 2002;99:7090–7095.
   PubMed Web of Science ®Google Scholar
• Rabenstein M, Hucklenbroich J, Willuweit A, et al. Osteopontin mediates survival, proliferation and migration of neural stem cells through the chemokine receptor CXCR4. Stem Cell Res Ther. 2015;6:99.
   PubMed Web of Science ®Google Scholar
• Tsai -H-H, Niu J, Munji R, et al. Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science. 2016;351:379–384.
   PubMed Web of Science ®Google Scholar
• Kim HJ, Shaker MR, Cho B, et al. Dynamin-related protein 1 controls the migration and neuronal differentiation of subventricular zone-derived neural progenitor cells. Sci Rep. 2015;5:15962.
   PubMed Web of Science ®Google Scholar
• Boockvar JA, Kapitonov D, Kapoor G, et al. Constitutive EGFR signaling confers a motile phenotype to neural stem cells. Mol Cell Neurosci. 2003;24:1116–1130.
   PubMed Web of Science ®Google Scholar
• Cohen ME, Fainstein N, Lavon I, et al. Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis. Stem Cell Res. 2014;13:227–239.
   PubMed Web of Science ®Google Scholar
• Codega P, Silva-Vargas V, Paul A, et al. Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron. 2014;82:545–559.
   PubMed Web of Science ®Google Scholar
• Llorens-Bobadilla E, Zhao S, Baser A, et al. Single-Cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell. 2015;17:329–340.
   PubMed Web of Science ®Google Scholar
• Kakita A, Goldman JE. Patterns and dynamics of SVZ cell migration in the postnatal forebrain: monitoring living progenitors in slice preparations. Neuron. 1999;23:461–472.
   PubMed Web of Science ®Google Scholar
• Gensert JM, Goldman JE. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron. 1997;19:197–203.
   PubMed Web of Science ®Google Scholar
• Pluchino S, Muzio L, Imitola J, et al. Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain. 2008;131:2564–2578.
   PubMed Web of Science ®Google Scholar
• Tepavčević V, Lazarini F, Alfaro-Cervello C, et al. Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis. J Clin Invest. 2011;121:4722–4734.
   PubMed Web of Science ®Google Scholar
• Guglielmetti C, Praet J, Rangarajan JR, et al. Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum. Neuroimage. 2014;86:99–110.
   PubMed Web of Science ®Google Scholar
• Menn B, Garcia-Verdugo JM, Yaschine C, et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci. 2006;26:7907–7918.
   PubMed Web of Science ®Google Scholar
• Manitt C, Colicos MA, Thompson KM, et al. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord. J Neurosci. 2001;21:3911–3922.
   PubMed Web of Science ®Google Scholar
• Bin JM, Rajasekharan S, Kuhlmann T, et al. Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration. Am J Pathol. 2013;183:673–680.
   PubMed Web of Science ®Google Scholar
• Prins M, Dutta R, Baselmans B, et al. Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients. Acta Neuropathol Commun. 2014;2:98.
   PubMedGoogle Scholar
• Moll NM, Cossoy MB, Fisher E, et al. Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis. Arch Neurol. 2009;66:44–53.
   PubMed Web of Science ®Google Scholar
• Tadagavadi RK, Wang W, Ramesh G. Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemiareperfusion injury. J Immunol. 2010;185:3750–3758.
   PubMed Web of Science ®Google Scholar
• Mirakaj V, Thix CA, Laucher S, et al. Netrin-1 dampens pulmonary inflammation during acute lung injury. Am J Respir Crit Care Med. 2010;181:815–824.
   PubMed Web of Science ®Google Scholar
• Einstein O, Fainstein N, Vaknin I, et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol. 2007;61:209–218.
   PubMed Web of Science ®Google Scholar
• Merzaban JS, Imitola J, Starossom SC, et al. Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis. Glycobiology. 2015;25:1392–1409.
   PubMed Web of Science ®Google Scholar
• Berkowitz AL, Miller MB, Mir SA, et al. Glioproliferative lesion of the spinal cord as a complication of “StemCell Tourism”. N Engl J Med. 2016;375:196–198.
   PubMed Web of Science ®Google Scholar
• Bowman M, Racke M, Kissel J, et al. Responsibilities of health care professionals in counseling and educating patients with incurable neurological diseases regarding “Stem Cell Tourism”: caveat emptor. JAMA Neurol. 2015;72:1342–1345.
   PubMed Web of Science ®Google Scholar
• Fancy SPJ, Baranzini SE, Zhao C, et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 2009;23:1571–1585.
   PubMed Web of Science ®Google Scholar
• Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4:147ra111.
   PubMed Web of Science ®Google Scholar
• Haines JD, Vidaurre OG, Zhang F, et al. Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors. Mult Scler. 2015;21:1655–1669.
   PubMed Web of Science ®Google Scholar
• John GR, Shankar SL, Shafit-Zagardo B, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med. 2002;8:1115–1121.
   PubMed Web of Science ®Google Scholar
• Seifert T, Bauer J, Weissert R, et al. Differential expression of sonic hedgehog immunoreactivity during lesion evolution in autoimmune encephalomyelitis. J Neuropathol Exp Neurol. 2005;64:404–411.
   PubMed Web of Science ®Google Scholar
• Wang Y, Imitola J, Rasmussen S, et al. Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis. Ann Neurol. 2008;64:417–427.
   PubMed Web of Science ®Google Scholar
• Williams A, Piaton G, Aigrot M-S, et al. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain. 2007;130:2554–2565.
   PubMed Web of Science ®Google Scholar
• Spassky N, de Castro F, Le Bras B, et al. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J Neurosci. 2002;22:5992–6004.
   PubMed Web of Science ®Google Scholar
• Back SA, Tuohy TMF, Chen H, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med. 2005;11:966–972.
   PubMed Web of Science ®Google Scholar
• Hu J-G, Lü H-Z, Wang Y-X, et al. BMP signaling mediates astrocyte differentiation of oligodendrocyte progenitor cells. Tohoku J Exp Med. 2010;222:195–200.
   PubMed Web of Science ®Google Scholar
• Simon C, Götz M, Dimou L. Progenitors in the adult cerebral cortex: cell cycle properties and regulation by physiological stimuli and injury. Glia. 2011;59:869–881.
   PubMed Web of Science ®Google Scholar
• Rafalski VA, Ho PP, Brett JO, et al. Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat Cell Biol. 2013;15:614–624.
   PubMed Web of Science ®Google Scholar
• Nakatani H, Martin E, Hassani H, et al. Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination. J Neurosci. 2013;33:9752–9768.
   PubMed Web of Science ®Google Scholar
• Sohn J, Natale J, Chew L-J, et al. Identification of Sox17 as a transcription factor that regulates oligodendrocyte development. J Neurosci. 2006;26:9722–9735.
   PubMed Web of Science ®Google Scholar
• Moll NMEA, Hong E, Fauveau M, et al. SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis. Glia. 2013;61:1659–1672.
   PubMed Web of Science ®Google Scholar
• Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954.
   PubMed Web of Science ®Google Scholar
• Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAFmutant melanoma. Nature. 2010;467:596–599.
   PubMed Web of Science ®Google Scholar
• Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516.
   PubMed Web of Science ®Google Scholar
• Elices MJ, Osborn L, Takada Y, et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990;60:577–584.
   PubMed Web of Science ®Google Scholar
• Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.
   PubMed Web of Science ®Google Scholar
• Basso AS, Frenkel D, Quintana FJ, et al. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest. 2008;118:1532–1543.
   PubMed Web of Science ®Google Scholar
• Perrin S. Preclinical research: make mouse studies work. Nature. 2014;507:423–425.
   PubMed Web of Science ®Google Scholar
• Orack JC, Deleidi M, Pitt D, et al. Concise review: modeling multiple sclerosis with stem cell biological platforms: toward functional validation of cellular and molecular phenotypes in inflammationinduced neurodegeneration. Stem Cells Transl Med. 2015;4:252–260.
   PubMed Web of Science ®Google Scholar