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Attempts to Overcome Remyelination Failure: Toward Opening New Therapeutic Avenues for Multiple Sclerosis

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Abstract

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath wrapped around the axons and eventual axon degeneration. The disease is pathologically heterogeneous; however, perhaps its most frustrating aspect is the lack of efficient regenerative response for remyelination. Current treatment strategies are based on anti-inflammatory or immunomodulatory medications that have the potential to reduce the numbers of newly evolving lesions. However, therapies are still required that can repair already damaged myelin for which current treatments are not effective. A prerequisite for the development of such new treatments is understanding the reasons for insufficient endogenous repair. This review briefly summarizes the currently suggested causes of remyelination failure in MS and possible solutions.

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Abbreviations

MS:

Multiple sclerosis

CNS:

Central nervous system

PL:

Proteolipid protein,

CXCL1:

Chemokine (C-X-C motif) ligand 1

sema3A:

Semaphorins 3A

LINGO-1:

Leucine-rich repeat and immunoglobulin domain containing NOGO receptor interacting protein 1

RXRs:

Retinoid X receptors

EAE:

Experimental autoimmune encephalomyelitis

NgR1 complex:

Nogo-66 receptor complex

References

  • Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD (2004) bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306(5704):2111–2115. doi:10.1126/science.1103709

    Article  CAS  PubMed  Google Scholar 

  • Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, Luo NL, Banine F, Liu Y, Chang A, Trapp BD, Bebo BF Jr, Rao MS, Sherman LS (2005) Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature Medicine 11(9):966–972. doi:10.1038/nm1279

    CAS  PubMed  Google Scholar 

  • Baer AS, Syed YA, Kang SU, Mitteregger D, Vig R, Ffrench-Constant C, Franklin RJ, Altmann F, Lubec G, Kotter MR (2009) Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain : A Journal of Neurology 132(Pt 2):465–481. doi:10.1093/brain/awn334

    Article  Google Scholar 

  • Bin JM, Rajasekharan S, Kuhlmann T, Hanes I, Marcal N, Han D, Rodrigues SP, Leong SY, Newcombe J, Antel JP, Kennedy TE (2013) Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration. The American Journal of Pathology 183(3):673–680. doi:10.1016/j.ajpath.2013.06.004

    Article  CAS  PubMed  Google Scholar 

  • Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, Wilson D, Xu Q, Raz E (2008) Control of chemokine-guided cell migration by ligand sequestration. Cell 132(3):463–473

    Article  CAS  PubMed  Google Scholar 

  • Boyd A, Zhang H, Williams A (2013) Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathologica 125(6):841–859. doi:10.1007/s00401-013-1112-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116(2):167–179

    Article  CAS  PubMed  Google Scholar 

  • Casaccia-Bonnefil P, Liu A (2003) Relationship between cell cycle molecules and onset of oligodendrocyte differentiation. Journal of Neuroscience Research 72(1):1–11. doi:10.1002/jnr.10565

    Article  CAS  PubMed  Google Scholar 

  • Charles P, Hernandez MP, Stankoff B, Aigrot MS, Colin C, Rougon G, Zalc B, Lubetzki C (2000) Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proceedings of the National Academy of Sciences of the United States of America 97(13):7585–7590. doi:10.1073/pnas.100076197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, Zalc B, Lubetzki C (2002) Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Brain : A Journal of Neurology 125(Pt 9):1972–1979

    Article  Google Scholar 

  • Chen ZJ, Ughrin Y, Levine JM (2002) Inhibition of axon growth by oligodendrocyte precursor cells. Molecular and Cellular Neurosciences 20(1):125–139. doi:10.1006/mcne.2002.1102

    Article  CAS  PubMed  Google Scholar 

  • Cohen RI, Rottkamp DM, Maric D, Barker JL, Hudson LD (2003) A role for semaphorins and neuropilins in oligodendrocyte guidance. Journal of Neurochemistry 85(5):1262–1278

    Article  CAS  PubMed  Google Scholar 

  • Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335 (6075):1503-1506.

  • Cunnea P, Mhaille AN, McQuaid S, Farrell M, McMahon J, FitzGerald U (2011) Expression profiles of endoplasmic reticulum stress-related molecules in demyelinating lesions and multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 17 (7):808-818. doi:10.1177/1352458511399114

  • Czopka T, Von Holst A, Schmidt G, Ffrench-Constant C, Faissner A (2009) Tenascin C and tenascin R similarly prevent the formation of myelin membranes in a RhoA-dependent manner, but antagonistically regulate the expression of myelin basic protein via a separate pathway. Glia 57(16):1790–1801. doi:10.1002/glia.20891

    Article  PubMed  Google Scholar 

  • Dai J, Bercury KK, Ahrendsen JT, Macklin WB (2015) Olig1 function is required for oligodendrocyte differentiation in the mouse brain. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 35(10):4386–4402. doi:10.1523/jneurosci.4962-14.2015

    Article  CAS  Google Scholar 

  • Dawson MR, Polito A, Levine JM, Reynolds R (2003) NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Molecular and Cellular Neurosciences 24(2):476–488

    Article  CAS  PubMed  Google Scholar 

  • Dehghan S, Hesaraki M, Soleimani M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M (2016) Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice. Neuroscience 318:178–189. doi:10.1016/j.neuroscience.2016.01.028

    Article  CAS  PubMed  Google Scholar 

  • Dehghan S, Javan M, Pourabdolhossein F, Mirnajafi-Zadeh J, Baharvand H (2012) Basic fibroblast growth factor potentiates myelin repair following induction of experimental demyelination in adult mouse optic chiasm and nerves. Journal of Molecular Neuroscience : MN 48(1):77–85. doi:10.1007/s12031-012-9777-6

    Article  CAS  PubMed  Google Scholar 

  • Diab A, Hussain RZ, Lovett-Racke AE, Chavis JA, Drew PD, Racke MK (2004) Ligands for the peroxisome proliferator-activated receptor-gamma and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 148(1–2):116–126. doi:10.1016/j.jneuroim.2003.11.010

    Article  CAS  PubMed  Google Scholar 

  • Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJ, Rowitch DH (2009) Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes & Development 23(13):1571–1585. doi:10.1101/gad.1806309

    Article  CAS  Google Scholar 

  • Feigenson K, Reid M, See J, Crenshaw EB 3rd, Grinspan JB (2009) Wnt signaling is sufficient to perturb oligodendrocyte maturation. Molecular and cellular neurosciences 42(3):255–265. doi:10.1016/j.mcn.2009.07.010

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Enright F, Andrews JL, Newell KA, Pantelis C, Huang XF (2014) Novel implications of Lingo-1 and its signaling partners in schizophrenia. Translational Psychiatry 4 (1):e348-. doi:10.1038/tp.2013.121

  • Fewou SN, Ramakrishnan H, Bussow H, Gieselmann V, Eckhardt M (2007) Down-regulation of polysialic acid is required for efficient myelin formation. The Journal of Biological Chemistry 282(22):16700–16711. doi:10.1074/jbc.M610797200

    Article  CAS  PubMed  Google Scholar 

  • Franceschini I, Vitry S, Padilla F, Casanova P, Tham TN, Fukuda M, Rougon G, Durbec P, Dubois-Dalcq M (2004) Migrating and myelinating potential of neural precursors engineered to overexpress PSA-NCAM. Molecular and Cellular Neurosciences 27(2):151–162. doi:10.1016/j.mcn.2004.05.006

    Article  CAS  PubMed  Google Scholar 

  • Fuss B, Wintergerst ES, Bartsch U, Schachner M (1993) Molecular characterization and in situ mRNA localization of the neural recognition molecule J1-160/180: a modular structure similar to tenascin. The Journal of Cell Biology 120(5):1237–1249

    Article  CAS  PubMed  Google Scholar 

  • Fyffe-Maricich SL, Karlo JC, Landreth GE, Miller RH (2011) The ERK2 Mitogen-Activated Protein Kinase Regulates the Timing of Oligodendrocyte Differentiation. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 31(3):843–850. doi:10.1523/jneurosci.3239-10.2011

    Article  CAS  Google Scholar 

  • Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58(4):760–772

    Article  CAS  Google Scholar 

  • Ghasemi-Kasman M, Hajikaram M, Baharvand H, Javan M (2015) MicroRNA-mediated in vitro and in vivo direct conversion of astrocytes to neuroblasts. PloS one 10(6):e0127878. doi:10.1371/journal.pone.0127878

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ghasemi-Kasman M, Zare L, Baharvand H, Javan M (2016) In vivo conversion of astrocytes to myelinating cells by miR-302/367 and Valproate to enhance myelin repair J TERM In press

  • Gutowski NJ, Newcombe J, Cuzner ML (1999) Tenascin-R and C in multiple sclerosis lesions: relevance to extracellular matrix remodelling. Neuropathology and Applied Neurobiology 25(3):207–214

    Article  CAS  PubMed  Google Scholar 

  • Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451(7182):1076–1081. doi:10.1038/nature06559

    Article  CAS  PubMed  Google Scholar 

  • Horner PJ, Power AE, Kempermann G, Kuhn HG, Palmer TD, Winkler J, Thal LJ, Gage FH (2000) Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 20(6):2218–2228

    CAS  Google Scholar 

  • Hosking MP, Tirotta E, Ransohoff RM, Lane TE (2010) CXCR2 signaling protects oligodendrocytes and restricts demyelination in a mouse model of viral-induced demyelination. PLoS One 5(6):e11340. doi:10.1371/journal.pone.0011340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron-Van Evercooren A, Chambon P, Ffrench-Constant C, Franklin RJ (2011a) Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience 14(1):45–53. doi:10.1038/nn.2702

    Article  CAS  PubMed  Google Scholar 

  • Huang JK, Jarjour AA, Oumesmar BN, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron-Van Evercooren A, Chambon P, Ffrench-Constant C, Franklin RJM (2011b) Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience 14(1):45–53. doi:10.1038/nn.2702

    Article  CAS  PubMed  Google Scholar 

  • Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O (2007) Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson’s disease models. Proceedings of the National Academy of Sciences of the United States of America 104(36):14430–14435. doi:10.1073/pnas.0700901104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishii A, Fyffe-Maricich SL, Furusho M, Miller RH, Bansal R (2012) ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 32(26):8855–8864. doi:10.1523/jneurosci.0137-12.2012

    Article  CAS  Google Scholar 

  • Islam MS, Tatsumi K, Okuda H, Shiosaka S, Wanaka A (2009) Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions. Neurochemistry International 54(3–4):192–198. doi:10.1016/j.neuint.2008.10.011

    Article  CAS  PubMed  Google Scholar 

  • John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF (2002) Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Medicine 8(10):1115–1121. doi:10.1038/nm781

    Article  CAS  PubMed  Google Scholar 

  • Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG (2012) Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One 7(5):e37589. doi:10.1371/journal.pone.0037589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keough MB, Rogers JA, Zhang P, Jensen SK, Stephenson EL, Chen T, Hurlbert MG, Lau LW, Rawji KS, Plemel JR, Koch M, Ling CC, Yong VW (2016) An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nature Communications 7:11312. doi:10.1038/ncomms11312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiernan BW, Gotz B, Faissner A, ffrench-Constant C (1996) Tenascin-C inhibits oligodendrocyte precursor cell migration by both adhesion-dependent and adhesion-independent mechanisms. Molecular and Cellular Neurosciences 7(4):322–335. doi:10.1006/mcne.1996.0024

    Article  CAS  PubMed  Google Scholar 

  • Kippert A, Fitzner D, Helenius J, Simons M (2009) Actomyosin contractility controls cell surface area of oligodendrocytes. BMC Cell Biology 10:71. doi:10.1186/1471-2121-10-71

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 26(1):328–332. doi:10.1523/jneurosci.2615-05.2006

    Article  CAS  Google Scholar 

  • Lariosa-Willingham KD, Rosler ES, Tung JS, Dugas JC, Collins TL, Leonoudakis D (2016) A high throughput drug screening assay to identify compounds that promote oligodendrocyte differentiation using acutely dissociated and purified oligodendrocyte precursor cells. BMC Research Notes. doi:10.1186/s13104-016-2220-2

    Google Scholar 

  • Lau LW, Cua R, Keough MB, Haylock-Jacobs S, Yong VW (2013) Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nature Reviews Neuroscience 14(10):722–729. doi:10.1038/nrn3550

    Article  CAS  PubMed  Google Scholar 

  • Lau LW, Keough MB, Haylock-Jacobs S, Cua R, Doring A, Sloka S, Stirling DP, Rivest S, Yong VW (2012) Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination. Annals of Neurology 72(3):419–432. doi:10.1002/ana.23599

    Article  CAS  PubMed  Google Scholar 

  • Lee X, Yang Z, Shao Z, Rosenberg SS, Levesque M, Pepinsky RB, Qiu M, Miller RH, Chan JR, Mi S (2007) NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 27(1):220–225. doi:10.1523/JNEUROSCI.4175-06.2007

    Article  CAS  Google Scholar 

  • Li H, Lu Y, Smith HK, Richardson WD (2007) Olig1 and Sox10 interact synergistically to drive myelin basic protein transcription in oligodendrocytes. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 27(52):14375–14382. doi:10.1523/jneurosci.4456-07.2007

    Article  CAS  Google Scholar 

  • Ligon KL, Fancy SP, Franklin RJ, Rowitch DH (2006) Olig gene function in CNS development and disease. Glia 54(1):1–10. doi:10.1002/glia.20273

    Article  PubMed  Google Scholar 

  • Liu L, Darnall L, Hu T, Choi K, Lane TE, Ransohoff RM (2010) Myelin repair is accelerated by inactivating CXCR2 on nonhematopoietic cells. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 30(27):9074–9083. doi:10.1523/jneurosci.1238-10.2010

    Article  CAS  Google Scholar 

  • Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Medicine 8(5):500–508. doi:10.1038/nm0502-500

    Article  CAS  PubMed  Google Scholar 

  • Maire CL, Wegener A, Kerninon C, Nait Oumesmar B (2010) Gain-of-function of Olig transcription factors enhances oligodendrogenesis and myelination. Stem Cells (Dayton, Ohio) 28 (9):1611-1622. doi:10.1002/stem.480

  • Manitt C, Kennedy TE (2002) Where the rubber meets the road: netrin expression and function in developing and adult nervous systems. Progress in Brain Research 137:425–442

    Article  CAS  PubMed  Google Scholar 

  • Massey JM, Amps J, Viapiano MS, Matthews RT, Wagoner MR, Whitaker CM, Alilain W, Yonkof AL, Khalyfa A, Cooper NG, Silver J, Onifer SM (2008) Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Experimental Neurology 209(2):426–445. doi:10.1016/j.expneurol.2007.03.029

    Article  CAS  PubMed  Google Scholar 

  • Mhaille AN, McQuaid S, Windebank A, Cunnea P, McMahon J, Samali A, FitzGerald U (2008) Increased expression of endoplasmic reticulum stress-related signaling pathway molecules in multiple sclerosis lesions. Journal of neuropathology and Experimental Neurology 67(3):200–211. doi:10.1097/NEN.0b013e318165b239

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, Wong WM, Wang L, Su H, Chu TH, Guo J, Zhang W, So KF, Pepinsky B, Shao Z, Graff C, Garber E, Jung V, Wu EX, Wu W (2007) LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nature Medicine 13(10):1228–1233. doi:10.1038/nm1664

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nature Neuroscience 7(3):221–228. doi:10.1038/nn1188

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, Chang J, Thill G, Levesque M, Zhang M, Hession C, Sah D, Trapp B, He Z, Jung V, McCoy JM, Pepinsky RB (2005) LINGO-1 negatively regulates myelination by oligodendrocytes. Nature Neuroscience 8(6):745–751. doi:10.1038/nn1460

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Miller RH, Tang W, Lee X, Hu B, Wu W, Zhang Y, Shields CB, Zhang Y, Miklasz S, Shea D, Mason J, Franklin RJ, Ji B, Shao Z, Chedotal A, Bernard F, Roulois A, Xu J, Jung V, Pepinsky B (2009) Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Annals of Neurology 65(3):304–315. doi:10.1002/ana.21581

    Article  CAS  PubMed  Google Scholar 

  • Miron VE, Kuhlmann T (1812) Antel JP (2011) Cells of the oligodendroglial lineage, myelination, and remyelination. Biochimica et Biophysica Acta 2:184–193. doi:10.1016/j.bbadis.2010.09.010

    Google Scholar 

  • Mohan H, Krumbholz M, Sharma R, Eisele S, Junker A, Sixt M, Newcombe J, Wekerle H, Hohlfeld R, Lassmann H, Meinl E (2010) Extracellular matrix in multiple sclerosis lesions: Fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathology (Zurich, Switzerland) 20 (5):966-975. doi:10.1111/j.1750-3639.2010.00399.x

  • Moll NM, Hong E, Fauveau M, Naruse M, Kerninon C, Tepavcevic V, Klopstein A, Seilhean D, Chew LJ, Gallo V, Nait Oumesmar B (2013) SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis. Glia 61(10):1659–1672. doi:10.1002/glia.22547

    Article  CAS  PubMed  Google Scholar 

  • Moreno S, Farioli-Vecchioli S, Ceru MP (2004) Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 123(1):131–145

    Article  CAS  PubMed  Google Scholar 

  • Moyon S, Dubessy AL, Aigrot MS, Trotter M, Huang JK, Dauphinot L, Potier MC, Kerninon C, Melik Parsadaniantz S, Franklin RJ, Lubetzki C (2015) Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 35(1):4–20. doi:10.1523/jneurosci.0849-14.2015

    Article  CAS  Google Scholar 

  • Mozafari S, Javan M, Sherafat MA, Mirnajafi-Zadeh J, Heibatollahi M, Pour-Beiranvand S, Tiraihi T, Ahmadiani A (2011) Analysis of structural and molecular events associated with adult rat optic chiasm and nerves demyelination and remyelination: possible role for 3rd ventricle proliferating cells. Neuromolecular Medicine 13(2):138–150. doi:10.1007/s12017-011-8143-0

    Article  CAS  PubMed  Google Scholar 

  • Mozafari S, Sherafat MA, Javan M, Mirnajafi-Zadeh J, Tiraihi T (2010) Visual evoked potentials and MBP gene expression imply endogenous myelin repair in adult rat optic nerve and chiasm following local lysolecithin induced demyelination. Brain Research 1351:50–56. doi:10.1016/j.brainres.2010.07.026

    Article  CAS  PubMed  Google Scholar 

  • Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC, Miller TE, Nevin ZS, Kantor C, Sargent A, Quick KL, Schlatzer DM, Tang H, Papoian R, Brimacombe KR, Shen M, Boxer MB, Jadhav A, Robinson AP, Podojil JR, Miller SD, Miller RH, Tesar PJ (2015) Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522(7555):216–220. doi:10.1038/nature14335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Napoli I, Neumann H (2010) Protective effects of microglia in multiple sclerosis. Experimental Neurology 225(1):24–28. doi:10.1016/j.expneurol.2009.04.024

    Article  PubMed  Google Scholar 

  • Narayanan SP, Flores AI, Wang F, Macklin WB (2009) Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 29(21):6860–6870. doi:10.1523/jneurosci.0232-09.2009

    Article  CAS  Google Scholar 

  • Naumann U, Cameroni E, Pruenster M, Mahabaleshwar H, Raz E, Zerwes H-G, Rot A, Thelen M (2010) CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS One 5(2):e9175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nickles D, Chen HP, Li MM, Khankhanian P, Madireddy L, Caillier SJ, Santaniello A, Cree BA, Pelletier D, Hauser SL, Oksenberg JR, Baranzini SE (2013) Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls. Human Molecular Genetics 22(20):4194–4205. doi:10.1093/hmg/ddt267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Omari KM, John GR, Sealfon SC, Raine CS (2005) CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain : A Journal of Neurology 128(Pt 5):1003–1015. doi:10.1093/brain/awh479

    Article  Google Scholar 

  • Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS (2009) Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1. The American Journal of Pathology 174(1):164–176. doi:10.2353/ajpath.2009.080350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel JR, McCandless EE, Dorsey D, Klein RS (2010) CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proceedings of the National Academy of Sciences 107(24):11062–11067

    Article  CAS  Google Scholar 

  • Patel JR, Williams JL, Muccigrosso MM, Liu L, Sun T, Rubin JB, Klein RS (2012) Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta neuropathologica 124(6):847–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pendleton JC, Shamblott MJ, Gary DS, Belegu V, Hurtado A, Malone ML, McDonald JW (2013) Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPsigma. Experimental neurology 247:113–121. doi:10.1016/j.expneurol.2013.04.003

    Article  CAS  PubMed  Google Scholar 

  • Piaton G, Aigrot MS, Williams A, Moyon S, Tepavcevic V, Moutkine I, Gras J, Matho KS, Schmitt A, Soellner H, Huber AB, Ravassard P, Lubetzki C (2011) Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system. Brain : A Journal of Neurology 134(Pt 4):1156–1167. doi:10.1093/brain/awr022

    Article  Google Scholar 

  • Pourabdolhossein F, Mozafari S, Morvan-Dubois G, Mirnajafi-Zadeh J, Lopez-Juarez A, Pierre-Simons J, Demeneix BA, Javan M (2014) Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm. PLoS One 9(9):e106378. doi:10.1371/journal.pone.0106378

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rajasekharan S, Bin JM, Antel JP, Kennedy TE (2010) A central role for RhoA during oligodendroglial maturation in the switch from netrin-1-mediated chemorepulsion to process elaboration. Journal of neurochemistry 113(6):1589–1597. doi:10.1111/j.1471-4159.2010.06717.x

    CAS  PubMed  Google Scholar 

  • Robinson S, Miller RH (1999) Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Developmental Biology 216(1):359–368. doi:10.1006/dbio.1999.9466

    Article  CAS  PubMed  Google Scholar 

  • Rodgers JM, Robinson AP, Miller SD (2013) Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis. Discovery Medicine 16(86):53–63

    PubMed  PubMed Central  Google Scholar 

  • Seifert T, Bauer J, Weissert R, Fazekas F, Storch MK (2007) Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination. Acta Neuropathologica 113(2):195–203. doi:10.1007/s00401-006-0170-9

    Article  CAS  PubMed  Google Scholar 

  • Selvaraju R, Bernasconi L, Losberger C, Graber P, Kadi L, Avellana-Adalid V, Picard-Riera N, Baron Van Evercooren A, Cirillo R, Kosco-Vilbois M, Feger G, Papoian R, Boschert U (2004) Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro. Molecular and Cellular Neurosciences 25(4):707–721. doi:10.1016/j.mcn.2003.12.014

    Article  CAS  PubMed  Google Scholar 

  • Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ, Casaccia-Bonnefil P (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neuroscience 11(9):1024–1034. doi:10.1038/nn.2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimizu T, Kagawa T, Wada T, Muroyama Y, Takada S, Ikenaka K (2005) Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Developmental Biology 282(2):397–410. doi:10.1016/j.ydbio.2005.03.020

    Article  CAS  PubMed  Google Scholar 

  • Siebert JR, Osterhout DJ (2011) The inhibitory effects of chondroitin sulfate proteoglycans on oligodendrocytes. Journal of Neurochemistry 119(1):176–188. doi:10.1111/j.1471-4159.2011.07370.x

    Article  CAS  PubMed  Google Scholar 

  • Siebert JR, Stelzner DJ, Osterhout DJ (2011) Chondroitinase treatment following spinal contusion injury increases migration of oligodendrocyte progenitor cells. Experimental Neurology 231(1):19–29. doi:10.1016/j.expneurol.2011.05.002

    Article  CAS  PubMed  Google Scholar 

  • Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T (2010) Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proceedings of the National Academy of Sciences of the United States of America 107(25):11555–11560. doi:10.1073/pnas.1006496107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spassky N, de Castro F, Le Bras B, Heydon K, Queraud-LeSaux F, Bloch-Gallego E, Chedotal A, Zalc B, Thomas JL (2002) Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 22(14):5992–6004.

    CAS  Google Scholar 

  • Starkey ML, Bartus K, Barritt AW, Bradbury EJ (2012) Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice. The European Journal of Neuroscience 36(12):3665–3678. doi:10.1111/ejn.12017

    Article  PubMed  PubMed Central  Google Scholar 

  • Steinbach K, McDonald CL, Reindl M, Schweigreiter R, Bandtlow C, Martin R (2011) Nogo-receptors NgR1 and NgR2 do not mediate regulation of CD4 T helper responses and CNS repair in experimental autoimmune encephalomyelitis. PLoS One 6(11):e26341. doi:10.1371/journal.pone.0026341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stidworthy MF, Genoud S, Li WW, Leone DP, Mantei N, Suter U, Franklin RJ (2004) Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination. Brain : A Journal of Neurology 127(Pt 9):1928–1941. doi:10.1093/brain/awh217

    Article  Google Scholar 

  • Stoffels JM, de Jonge JC, Stancic M, Nomden A, van Strien ME, Ma D, Siskova Z, Maier O, Ffrench-Constant C, Franklin RJ, Hoekstra D, Zhao C, Baron W (2013) Fibronectin aggregation in multiple sclerosis lesions impairs remyelination. Brain : A Journal of Neurology 136(Pt 1):116–131. doi:10.1093/brain/aws313

    Article  Google Scholar 

  • Stolt CC, Lommes P, Friedrich RP, Wegner M (2004) Transcription factors Sox8 and Sox10 perform non-equivalent roles during oligodendrocyte development despite functional redundancy. Development (Cambridge, England) 131 (10):2349-2358. doi:10.1242/dev.01114

  • Stumm R, Kolodziej A, Schulz S, Kohtz JD, Hollt V (2007) Patterns of SDF-1alpha and SDF-1gamma mRNAs, migration pathways, and phenotypes of CXCR4-expressing neurons in the developing rat telencephalon. The Journal of Comparative Neurology 502(3):382–399. doi:10.1002/cne.21336

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto Y, Taniguchi M, Yagi T, Akagi Y, Nojyo Y, Tamamaki N (2001) Guidance of glial precursor cell migration by secreted cues in the developing optic nerve. Development (Cambridge, England) 128 (17):3321-3330

  • Sun JJ, Ren QG, Xu L, Zhang ZJ (2015) LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice. Scientific Reports. doi:10.1038/srep14235

    Google Scholar 

  • Syed YA, Hand E, Mobius W, Zhao C, Hofer M, Nave KA, Kotter MR (2011) Inhibition of CNS remyelination by the presence of semaphorin 3A. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 31(10):3719–3728. doi:10.1523/jneurosci.4930-10.2011

    Article  CAS  Google Scholar 

  • Tepavcevic V, Kerninon C, Aigrot MS, Meppiel E, Mozafari S, Arnould-Laurent R, Ravassard P, Kennedy TE, Nait-Oumesmar B, Lubetzki C (2014) Early netrin-1 expression impairs central nervous system remyelination. Annals of Neurology 76(2):252–268. doi:10.1002/ana.24201

    Article  CAS  PubMed  Google Scholar 

  • Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP, de Jong R, Brosofsky K, Ray S, Xu L, Zhao J, Parr E, Cadavid D (2014) Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurology (R) Neuroimmunology & Neuroinflammation 1 (2):e18. doi:10.1212/nxi.0000000000000018

  • Tsai HH, Frost E, To V, Robinson S, Ffrench-Constant C, Geertman R, Ransohoff RM, Miller RH (2002) The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110(3):373–383

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA (1998) Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21(1):63–75

    Article  PubMed  Google Scholar 

  • Wheeler NA, Fuss B (2016) Extracellular cues influencing oligodendrocyte differentiation and (re)myelination. Experimental Neurology 283 (Pt B):512-530. doi:10.1016/j.expneurol. 2016.03.019

  • Williams A, Piaton G, Aigrot MS, Belhadi A, Theaudin M, Petermann F, Thomas JL, Zalc B, Lubetzki C (2007) Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain : A Journal of Neurology 130(Pt 10):2554–2565. doi:10.1093/brain/awm202

    Article  Google Scholar 

  • Woodruff RH, Franklin RJ (1999) Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study. Glia 25(3):216–228

    Article  CAS  PubMed  Google Scholar 

  • Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, Ng SW, Kilpatrick TJ, Merson TD (2014) Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 34(42):14128–14146. doi:10.1523/jneurosci.3491-13.2014

    Article  CAS  Google Scholar 

  • Yang Y, Liu Y, Wei P, Peng H, Winger R, Hussain RZ, Ben LH, Cravens PD, Gocke AR, Puttaparthi K, Racke MK, McTigue DM, Lovett-Racke AE (2010) Silencing Nogo-A promotes functional recovery in demyelinating disease. Annals of Neurology 67(4):498–507. doi:10.1002/ana.21935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Argaw AT, Gurfein BT, Zameer A, Snyder BJ, Ge C, Lu QR, Rowitch DH, Raine CS, Brosnan CF, John GR (2009) Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proceedings of the National Academy of Sciences of the United States of America 106(45):19162–19167. doi:10.1073/pnas.0902834106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao C, Fancy SP, ffrench-Constant C, Franklin RJ (2008) Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiology of Disease 31(2):209–217. doi:10.1016/j.nbd.2008.04.007

    Article  PubMed  CAS  Google Scholar 

  • Zhao C, Li WW, Franklin RJ (2006) Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination. Neurobiology of Aging 27(9):1298–1307. doi:10.1016/j.neurobiolaging.2005.06.008

    Article  CAS  PubMed  Google Scholar 

  • 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 

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Acknowledgements

Authors are thankful to Tarbiat Modares University, Royan institute, and Iranian Science Foundation for their support.

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Authors and Affiliations

  1. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran

    Mahsa Motavaf & Majid Sadeghizadeh

  2. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran, Islamic Republic of Iran

    Mohammad Javan

  3. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Islamic Republic of Iran

    Mohammad Javan

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  1. Mahsa Motavaf
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Motavaf, M., Sadeghizadeh, M. & Javan, M. Attempts to Overcome Remyelination Failure: Toward Opening New Therapeutic Avenues for Multiple Sclerosis. Cell Mol Neurobiol 37, 1335–1348 (2017). https://doi.org/10.1007/s10571-017-0472-6

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