Abstract
Multiple sclerosis (MS) is an autoimmune disease that leads to oligodendrocyte loss and subsequent demyelination of the adult central nervous system (CNS). The pathology is characterized by transient phases of recovery during which remyelination can occur as a result of resident oligodendroglial precursor and stem/progenitor cell activation. However, myelin repair efficiency remains low urging the development of new therapeutical approaches that promote remyelination activities. Current MS treatments target primarily the immune system in order to reduce the relapse rate and the formation of inflammatory lesions, whereas no therapies exist in order to regenerate damaged myelin sheaths. During the last few years, several transplantation studies have been conducted with adult neural stem/progenitor cells and glial precursor cells to evaluate their potential to generate mature oligodendrocytes that can remyelinate axons. In parallel, modulation of the endogenous progenitor niche by neural and mesenchymal stem cell transplantation with the aim of promoting CNS progenitor differentiation and myelination has been studied. Here, we summarize these findings and discuss the properties and consequences of the various molecular and cell-mediated remyelination approaches. Moreover, we address age-associated intrinsic cellular changes that might influence the regenerative outcome. We also evaluate the extent to which these experimental treatments might increase the regeneration capacity of the demyelinated human CNS and hence be turned into future therapies.
Similar content being viewed by others
References
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822
Aguirre A, Dupree JL, Mangin JM, Gallo V (2007) A functional role for EGFR signaling in myelination and remyelination. Nat Neurosci 10:990–1002
Aharonowiz M, Einstein O, Fainstein N, Lassmann H, Reubinoff B, Ben-Hur T (2008) Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis. PLoS One 3:e3145
Ahlenius H, Visan V, Kokaia M, Lindvall O, Kokaia Z (2009) Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain. J Neurosci 29:4408–4419
Aizawa K, Ageyama N, Terao K, Hisatsune T (2011) Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus. Neurobiol Aging 32:140–150
Akiyama Y, Honmou O, Kato T, Uede T, Hashi K, Kocsis JD (2001) Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp Neurol 167:27–39
Aktas O, Kieseier B, Hartung HP (2010) Neuroprotection, regeneration and immunomodulation: broadening the therapeutic repertoire in multiple sclerosis. Trends Neurosci 33:140–152
Altman J, Das GD (1964) Autoradiographic examination of the effects of enriched environment on the rate of glial multiplication in the adult rat brain. Nature 204:1161–1163
Altman J, Das G (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335
Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2:287–293
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973
Archer DR, Cuddon PA, Lipsitz D, Duncan ID (1997) Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nat Med 3:54–59
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 306:2111–2115
Awad A, Stüve O (2010) Multiple sclerosis in the elderly patient. Drugs Aging 27:283–294
Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ (1998) Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—similarities to astrocyte grafts. Proc Natl Acad Sci USA 95:3908–3913
Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD, Miller RH (2009) Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57:1192–1203
Barhum Y, Gai-Castro S, Bahat-Stromza M, Barzilay R, Melamed E, Offen D (2010) Intracerebroventricular transplantation of human mesenchymal stem cells induced to secrete neurotrophic factors attenuates clinical symptoms in a mouse model of multiple sclerosis. J Mol Neurosci 41:129–137
Barres BA, Burne JF, Holtmann B, Thoenen H, Sendtner M, Raff MC (1996) Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol Cell Neurosci 8:146–156
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 41:73–80
Bergman RJ, Gazit D, Kahn AJ, Gruber H, McDougall S, Hahn TJ (1996) Age-related changes in osteogenic stem cells in mice. J Bone Miner Res 11:568–577
Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123:1174–1183
Blakemore WF, Gilson JM, Crang AJ (2000) Transplanted glial cells migrate over a greater distance and remyelinate demyelinated lesions more rapidly than endogenous remyelinating cells. J Neurosci Res 61:288–294
Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7:14
Bork S, Pfister S, Witt H, Horn P, Korn B, Ho AD, Wagner W (2010) DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 9:54–63
Bronnum-Hansen H, Koch-Henriksen N, Stenager E (2004) Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain 127:844–850
Bruce CC, Zhao C, Franklin RJ (2010) Remyelination—an effective means of neuroprotection. Horm Behav 57:56–62
Brüstle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID, McKay RD (1999) Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285:754–756
Bunge MB, Bunge RP, Ris H (1961) Ultrastructural study of remyelination in an experimental lesion in adult cat spinal cord. J Biophys Biochem Cytol 10:67–94
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 USA 107:11068–11073
Carleton A, Petreanu LT, Lansford R, Alvarez-Buylla A, Lledo P-M (2003) Becoming a new neuron in the adult olfactory bulb. Nat Neurosci 6:507–518
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 20:6404–6412
Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173
Chari DM, Crang AJ, Blakemore WF (2003) Decline in rate of colonization of oligodendrocyte progenitor cell (OPC)-depleted tissue by adult OPCs with age. J Neuropathol Exp Neurol 62:908–916
Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res 38:215–224
Cho JS, Park HW, Park SK, Roh S, Kang SK, Paik KS, Chang MS (2009) Transplantation of mesenchymal stem cells enhances axonal outgrowth and cell survival in an organotypic spinal cord slice culture. Neurosci Lett 454:43–48
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760–764
Couillard-Despres S, Winner B, Karl C, Lindemann G, Schmid P, Aigner R, Laemke J, Bogdahn U, Winkler J, Bischofberger J, Aigner L (2006) Targeted transgene expression in neuronal precursors: watching young neurons in the old brain. Eur J Neurosci 24:1535–1545
Couillard-Despres S, Wuertinger C, Kandasamy M, Caioni M, Stadler K, Aigner R, Bogdahn U, Aigner L (2009) Ageing abolishes the effects of fluoxetine on neurogenesis. Mol Psychiatry 14:856–864
Cristofanilli M, Harris VK, Zigelbaum A, Goossens AM, Lu A, Rosenthal H, Sadiq SA (2011) Mesenchymal stem cells enhance the engraftment and myelinating ability of allogeneic oligodendrocyte progenitors in dysmyelinated mice. Stem Cells Dev 20:2065-2076
Crockett DP, Burshteyn M, Garcia C, Muggironi M, Casaccia-Bonnefil P (2005) Number of oligodendrocyte progenitors recruited to the lesioned spinal cord is modulated by the levels of the cell cycle regulatory protein p27Kip-1. Glia 49:301–308
Dawson MR, Levine JM, Reynolds R (2000) NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors? J Neurosci Res 61:471–479
Deng W, Obrocka M, Fischer I, Prockop DJ (2001) In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 282:148–152
Doetsch F (2003a) The glial identity of neural stem cells. Nat Neurosci 6:1127–1134
Doetsch F (2003b) A niche for adult neural stem cells. Curr Opin Genet Dev 13:543–550
Doetsch F, Alvarez-Buylla A (1996) Network of tangential pathways for neuronal migration in adult mammalian brain. Proc Natl Acad Sci USA 93:14895–14900
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716
Doucette JR, Jiao R, Nazarali AJ (2010) Age-related and cuprizone-induced changes in myelin and transcription factor gene expression and in oligodendrocyte cell densities in the rostral corpus callosum of mice. Cell Mol Neurobiol 30:607–629
Ebers GC, Sadovnick AD (1993) The geographic distribution of multiple sclerosis: a review. Neuroepidemiology 12:1–5
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 24:1074–1082
Einstein O, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Polyzoidou E, Lavon I, Milonas I, Karussis D, Abramsky O, Ben-Hur T (2006) Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis. Exp Neurol 198:275–284
Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, Lavon I, Baniyash M, Lassmann H, Ben-Hur T (2007) Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 61:209–218
Einstein O, Friedman-Levi Y, Grigoriadis N, Ben-Hur T (2009) Transplanted neural precursors enhance host brain-derived myelin regeneration. J Neurosci 29:15694–15702
Encinas JM, Michurina TV, Peunova N, Park JH, Tordo J, Peterson DA, Fishell G, Koulakov A, Enikolopov G (2011) Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8:566–579
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 27:247–254
Ffrench-Constant C, Raff MC (1986a) The oligodendrocyte-type-2 astrocyte cell lineage is specialized for myelination. Nature 323:335–338
Ffrench-Constant C, Raff MC (1986b) Proliferating bipotential glial progenitor cells in adult rat optic nerve. Nature 319:499–502
Flici H, Erkosar B, Komonyi O, Karatas OF, Laneve P, Giangrande A (2011) Gcm/Glide-dependent conversion into glia depends on neural stem cell age, but not on division, triggering a chromatin signature that is conserved in vertebrate glia. Development 138:4167–4178
Fox RJ, Ransohoff RM (2004) New directions in MS therapeutics: vehicles of hope. Trends Immunol 25:632–636
Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714
Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855
Franklin RJ, Kotter MR (2008) The biology of CNS remyelination: the key to therapeutic advances. J Neurol 255 (Suppl 1):19–25
Franklin RJ, Bayley SA, Milner R, Ffrench-Constant C, Blakemore WF (1995) Differentiation of the O-2A progenitor cell line CG-4 into oligodendrocytes and astrocytes following transplantation into glia-deficient areas of CNS white matter. Glia 13:39–44
Freedman MS, Bar-Or A, Atkins HL, Karussis D, Frassoni F, Lazarus H, Scolding N, Slavin S, Le Blanc K, Uccelli A (2010) The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler 16:503–510
Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438
Gala K, Burdzinska A, Idziak M, Makula J, Paczek L (2011) Characterization of bone-marrow-derived rat mesenchymal stem cells depending on donor age. Cell Biol Int 35:1055–1062
Gates MA, Thomas LB, Howard EM, Laywell ED, Sajin B, Faissner A, Gotz B, Silver J, Steindler DA (1995) Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres. J Comp Neurol 361:249–266
Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A (2007) Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 61:219–227
Gilson J, Blakemore WF (1993) Failure of remyelination in areas of demyelination produced in the spinal cord of old rats. Neuropathol Appl Neurobiol 19:173–181
Gomez-Garcia AO, Fernandez-Concepcion O, Milan-Ginjauma E (1997) Clinical-epidemiological characteristics of late onset multiple sclerosis. Rev Neurol 25:1863–1866
Gonzalez-Perez O, Romero-Rodriguez R, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A (2009) Epidermal growth factor induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells 27:2032–2043
Gordon D, Pavlovska G, Glover CP, Uney JB, Wraith D, Scolding NJ (2008) Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration. Neurosci Lett 448:71–73
Gordon D, Pavlovska G, Uney JB, Wraith DC, Scolding NJ (2010) Human mesenchymal stem cells infiltrate the spinal cord, reduce demyelination, and localize to white matter lesions in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol 69:1087–1095
Göttle P, Kremer D, Jander S, Odemis V, Engele J, Hartung HP, Küry P (2010) Activation of CXCR7 receptor promotes oligodendroglial cell maturation. Ann Neurol 68:915–924
Grigoriadis N, Lourbopoulos A, Lagoudaki R, Frischer JM, Polyzoidou E, Touloumi O, Simeonidou C, Deretzi G, Kountouras J, Spandou E, Kotta K, Karkavelas G, Tascos N, Lassmann H (2011) Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis. Exp Neurol 230:78–89
Gritti A, Frolichsthal-Schoeller P, Galli R, Parati EA, Cova L, Pagano SF, Bjornson CR, Vescovi AL (1999) Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. J Neurosci 19:3287–3297
Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362:453–455
Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP (2006) Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pract Neurol 2:201–211
Hinks GL, Franklin RJ (2000) Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 16:542–556
Hooge JP, Redekop WK (1992) Multiple sclerosis with very late onset. Neurology 42:1907–1910
Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ (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 USA 101:18117–18122
Jablonska B, Aguirre A, Raymond M, Szabo G, Kitabatake Y, Sailor KA, Ming GL, Song H, Gallo V (2010) Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci 13:541–550
Jackson EL, Garcia-Verdugo JM, Gil-Perotin S, Roy M, Quinones-Hinojosa A, VandenBerg S, Alvarez-Buylla A (2006) PDGFR[alpha]-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51:187–199
Jeffery ND, Blakemore WF (1997) Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120:27–37
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 11:888–893
Ji JF, He BP, Dheen ST, Tay SS (2004) Expression of chemokine receptors CXCR4, CCR2, CCR5 and CX3CR1 in neural progenitor cells isolated from the subventricular zone of the adult rat brain. Neurosci Lett 355:236–240
Kabat EA, Wolf A, Bezer AE, Murray JP (1951) Studies on acute disseminated encephalomyelitis produced experimentally in rhesus monkeys. J Exp Med 93:615–633
Kaplan MS, Hinds JW (1977) Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197:1092–1094
Kassem M, Marie PJ (2011) Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell 10:191–197
Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D (2008) Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 65:753–761
Keirstead HS, Levine JM, Blakemore WF (1998) Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia 22:161–170
Kemp K, Gordon D, Wraith DC, Mallam E, Hartfield E, Uney J, Wilkins A, Scolding N (2010) Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells. Neuropathol Appl Neurobiol 37:166–178
Kerschensteiner M, Stadelmann C, Dechant G, Wekerle H, Hohlfeld R (2003) Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann Neurol 53:292–304
Kis B, Rumberg B, Berlit P (2008) Clinical characteristics of patients with late-onset multiple sclerosis. J Neurol 255:697–702
Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96:10711–10716
Kornek B, Lassmann H (2003) Neuropathology of multiple sclerosis—new concepts. Brain Res Bull 61:321–326
Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332
Kremer D, Heinen A, Jadasz J, Göttle P, Zimmermann K, Zickler P, Jander S, Hartung HP, Küry P (2009) p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis and interferes with oligodendroglial maturation. Proc Natl Acad Sci USA 106:9087–9092
Kremer D, Aktas O, Hartung HP, Küry P (2011) The complex world of oligodendroglial differentiation inhibitors. Ann Neurol 69:602–618
Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184
Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB (2002) T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu Rev Immunol 20:101–123
Kuhlmann T, Miron V, Cuo Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131:1749–1758
Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033
Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH (1997) Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17:5820–5829
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452
Lanza C, Morando S, Voci A, Canesi L, Principato MC, Serpero LD, Mancardi G, Uccelli A, Vergani L (2009) Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. J Neurochem 110:1674–1684
Larsen PH, Wells JE, Stallcup WB, Opdenakker G, Yong VW (2003) Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J Neurosci 23:11127–11135
Lassmann H (1998) Neuropathology in multiple sclerosis: new concepts. Mult Scler 4:93–98
Lassmann H (1999) Mechanisms of demyelination and tissue damage in multiple sclerosis. Acta Neurol Belg 99:6–10
Lassmann H (2007a) Experimental models of multiple sclerosis. Rev Neurol (Paris) 163:651–655
Lassmann H (2007b) Multiple sclerosis: is there neurodegeneration independent from inflammation? J Neurol Sci 259:3–6
Lassmann H, Bruck W, Lucchinetti C, Rodriguez M (1997) Remyelination in multiple sclerosis. Mult Scler 3:133–136
Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA (2000) Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA 97:13883–13888
Levine JM, Reynolds R (1999) Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp Neurol 160:333–347
Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell in health and disease. Trends Neurosci 24:39–47
Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z (2000) Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:1311–1319
Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M (2001) Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 316:67–70
Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, Zhao X (2010) Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6:433–444
Liu XJ, Zhang JF, Sun B, Peng HS, Kong QF, Bai SS, Liu YM, Wang GY, Wang JH, Li HL (2009) Reciprocal effect of mesenchymal stem cell on experimental autoimmune encephalomyelitis is mediated by transforming growth factor-beta and interleukin-6. Clin Exp Immunol 158:37–44
Lois C, Alvarez-Buylla A (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264:1145–1148
Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005) DNA repair, genome stability, and aging. Cell 120:497–512
Lu P, Jones LL, Snyder EY, Tuszynski MH (2003) Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol 181:115–129
Lu P, Blesch A, Tuszynski MH (2004) Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 77:174–191
Lu Z, Hu X, Zhu C, Wang D, Zheng X, Liu Q (2009) Overexpression of CNTF in mesenchymal stem cells reduces demyelination and induces clinical recovery in experimental autoimmune encephalomyelitis mice. J Neuroimmunol 206:58–69
Lublin FD, Reingold SC (1996) 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 46:907–911
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (1999) A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122:2279–2295
Luskin MB (1993) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11:173–189
Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, Mandel G, Goodman RH (2010) microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci USA 107:20382–20387
Mahmood A, Lu D, Wang L, Li Y, Lu M, Chopp M (2001) Treatment of traumatic brain injury in female rats with intravenous administration of bone marrow stromal cells. Neurosurgery 49:1196–1203
Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E, Fagioli F (2006) Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem 97:744–754
Martino G, Franklin RJ, Van Evercooren AB, Kerr DA (2010) Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol 6:247–255
Maslov AY, Barone TA, Plunkett RJ, Pruitt SC (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733
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 26:7907–7918
Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250
Minguell JJ, Erices A, Conget P (2001) Mesenchymal stem cells. Exp Biol Med (Maywood) 226:507–520
Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B (2004) Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3:379–389
Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452
Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, Kooy D van der (1994) Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082
Munoz-Elias G, Woodbury D, Black IB (2003) Marrow stromal cells, mitosis, and neuronal differentiation: stem cell and precursor functions. Stem Cells 21:437–448
Murtie JC, Zhou YX, Le TQ, Vana AC, Armstrong RC (2005) PDGF and FGF2 pathways regulate distinct oligodendrocyte lineage responses in experimental demyelination with spontaneous remyelination. Neurobiol Dis 19:171–182
Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Van Evercooren AB (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 11:4357–4366
Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R, Baron-Van Evercooren A (2007) Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci USA 104:4694–4699
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49
Neuhuber B, Gallo G, Howard L, Kostura L, Mackay A, Fischer I (2004) Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype. J Neurosci Res 77:192–204
Nishino J, Kim I, Chada K, Morrison SJ (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135:227–239
Noseworthy J, Paty D, Wonnacott T, Feasby T, Ebers G (1983) Multiple sclerosis after age 50. Neurology 33:1537–1544
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952
Padovan CS, Jahn K, Birnbaum T, Reich P, Sostak P, Strupp M, Straube A (2003) Expression of neuronal markers in differentiated marrow stromal cells and CD133+ stem-like cells. Cell Transplant 12:839–848
Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494
Park Y, Gerson SL (2005) DNA repair defects in stem cell function and aging. Annu Rev Med 56:495–508
Patel JR, McCandless EE, Dorsey D, Klein RS (2010) CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci USA 107:11062–11067
Peters A, Sethares C (2003) Is there remyelination during aging of the primate central nervous system? J Comp Neurol 460:238–254
Peters A, Sethares C, Moss MB (2010) How the primate fornix is affected by age. J Comp Neurol 518:3962–3980
Picard-Riera N, Decker L, Delarasse C, Goude K, Nait-Oumesmar B, Liblau R, Pham-Dinh D, Evercooren AB (2002) Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci USA 99:13211–13216
Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688–694
Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G (2005) Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436:266–271
Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, t Hart B, Vescovi A, Martino G (2009a) Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol 66:343–354
Pluchino S, Zanotti L, Brambilla E, Rovere-Querini P, Capobianco A, Alfaro-Cervello C, Salani G, Cossetti C, Borsellino G, Battistini L, Ponzoni M, Doglioni C, Garcia-Verdugo JM, Comi G, Manfredi AA, Martino G (2009b) Immune regulatory neural stem/precursor cells protect from central nervous system autoimmunity by restraining dendritic cell function. PLoS One 4:e5959
Politi LS, Bacigaluppi M, Brambilla E, Cadioli M, Falini A, Comi G, Scotti G, Martino G, Pluchino S (2007) Magnetic-resonance-based tracking and quantification of intravenously injected neural stem cell accumulation in the brains of mice with experimental multiple sclerosis. Stem Cells 25:2583–2592
Polliack ML, Barak Y, Achiron A (2001) Late-onset multiple sclerosis. J Am Geriatr Soc 49:168–171
Praag H van, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034
Rafei M, Birman E, Forner K, Galipeau J (2009a) Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol Ther 17:1799–1803
Rafei M, Campeau PM, Aguilar-Mahecha A, Buchanan M, Williams P, Birman E, Yuan S, Young YK, Boivin MN, Forner K, Basik M, Galipeau J (2009b) Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner. J Immunol 182:5994–6002
Raff MC, Miller RH, Noble M (1983) A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303:390–396
Raff MC, Williams BPa, Miller RH (1984) The in vitro differentiation of a bipotential glial progenitor cell. EMBO J 3:1857–1864
Ragonese P, Aridon P, Salemi G, D'Amelio M, Savettieri G (2008) Mortality in multiple sclerosis: a review. Eur J Neurol 15:123–127
Rampon C, Weiss N, Deboux C, Chaverot N, Miller F, Buchet D, Tricoire-Leignel H, Cazaubon S, Baron-Van Evercooren A, Couraud PO (2008) Molecular mechanism of systemic delivery of neural precursor cells to the brain: assembly of brain endothelial apical cups and control of transmigration by CD44. Stem Cells 26:1673–1682
Redwine JM, Armstrong RC (1998) In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination. J Neurobiol 37:413–428
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 31:523–536
Rismanchi N, Floyd CL, Berman RF, Lyeth BG (2003) Cell death and long-term maintenance of neuron-like state after differentiation of rat bone marrow stromal cells: a comparison of protocols. Brain Res 991:46–55
Rist JM, Franklin RJ (2008) Taking ageing into account in remyelination-based therapies for multiple sclerosis. J Neurol Sci 274:64–67
Rivera FJ, Couillard-Despres S, Pedre X, Ploetz S, Caioni M, Lois C, Bogdahn U, Aigner L (2006a) Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells. Stem Cells 24:2209–2219
Rivera FJ, Sierralta WD, Minguell JJ, Aigner L (2006b) Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells. Neurosci Lett 406:49–54
Rivera FJ, Kandasamy M, Couillard-Despres S, Caioni M, Sanchez R, Huber C, Weidner N, Bogdahn U, Aigner L (2008) Oligodendrogenesis of adult neural progenitors: differential effects of ciliary neurotrophic factor and mesenchymal stem cell derived factors. J Neurochem 107:832–843
Rivera FJ, Siebzehnrubl FA, Kandasamy M, Couillard-Despres S, Caioni M, Poehler AM, Berninger B, Sandner B, Bogdahn U, Goetz M, Bluemcke I, Weidner N, Aigner L (2009) Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cell Physiol Biochem 24:317–324
Rivera FJ, Steffenhagen C, Kremer D, Kandasamy M, Sandner B, Couillard-Despres S, Weidner N, Küry P, Aigner L (2010) Deciphering the oligodendrogenic program of neural progenitors: cell intrinsic and extrinsic regulators. Stem Cells Dev 19:595–606
Rivers TM, Sprunt DH, Berry GP (1933) Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 58:39–53
Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ (2012) Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96–103
Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256
Schallmoser K, Bartmann C, Rohde E, Bork S, Guelly C, Obenauf AC, Reinisch A, Horn P, Ho AD, Strunk D, Wagner W (2010) Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions. Haematologica 95:867–874
Schonrock LM, Kuhlmann T, Adler S, Bitsch A, Bruck W (1998) Identification of glial cell proliferation in early multiple sclerosis lesions. Neuropathol Appl Neurobiol 24:320–330
Scolding N, Franklin R, Stevens S, Heldin CH, Compston A, Newcombe J (1998) Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121:2221–2228
Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26:212–222
Seri B, Herrera DG, Gritti A, Ferron S, Collado L, Vescovi A, Garcia-Verdugo JM, Alvarez-Buylla A (2006) Composition and organization of the SCZ: a large germinal layer containing neural stem cells in the adult mammalian brain. Cereb Cortex 16 (Suppl 1):i103–i111
Setzu A, Lathia JD, Zhao C, Wells K, Rao MS, Ffrench-Constant C, Franklin RJ (2006) Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 54:297–303
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. Nat Neurosci 11:1024–1034
Sher F, Dam G van, Boddeke E, Copray S (2009) Bioluminescence imaging of Olig2-neural stem cells reveals improved engraftment in a demyelination mouse model. Stem Cells 27:1582–1591
Shetty AK, Rao MS, Hattiangady B (2008) Behavior of hippocampal stem/progenitor cells following grafting into the injured aged hippocampus. J Neurosci Res 86:3062–3074
Shields SA, Gilson JM, Blakemore WF, Franklin RJ (1999) Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 28:77–83
Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F (2010) Multiple sclerosis—candidate mechanisms underlying CNS atrophy. Trends Neurosci 33:202–210
Silva Meirelles L da, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213
Smith PM, Blakemore WF (2000) Porcine neural progenitors require commitment to the oligodendrocyte lineage prior to transplantation in order to achieve significant remyelination of demyelinated lesions in the adult CNS. Eur J Neurosci 12:2414–2424
Smith KJ, McDonald WI, Blakemore WF (1979) Restoration of secure conduction by central demyelination. Trans Am Neurol Assoc 104:25–29
Sospedra M, Martin R (2005) Antigen-specific therapies in multiple sclerosis. Int Rev Immunol 24:393–413
Stolzing A, Scutt A (2006) Age-related impairment of mesenchymal progenitor cell function. Aging Cell 5:213–224
Syed YA, Baer AS, Lubec G, Hoeger H, Widhalm G, Kotter MR (2008) Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins. Neurosurg Focus 24:E5
Talbott JF, Cao Q, Bertram J, Nkansah M, Benton RL, Lavik E, Whittemore SR (2007) CNTF promotes the survival and differentiation of adult spinal cord-derived oligodendrocyte precursor cells in vitro but fails to promote remyelination in vivo. Exp Neurol 204:485–489
Tang DG, Tokumoto YM, Raff MC (2000) Long-term culture of purified postnatal oligodendrocyte precursor cells. Evidence for an intrinsic maturation program that plays out over months. J Cell Biol 148:971–984
Temple S (2001) The development of neural stem cells. Nature 414:112–117
Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545
Tokalov SV, Gruener S, Schindler S, Iagunov AS, Baumann M, Abolmaali ND (2007) A number of bone marrow mesenchymal stem cells but neither phenotype nor differentiation capacities changes with age of rats. Mol Cells 24:255–260
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 338:278–285
Uccelli A, Zappia E, Benvenuto F, Frassoni F, Mancardi G (2006) Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opin Biol Ther 6:17–22
Uccelli A, Pistoia V, Moretta L (2007) Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol 28:219–226
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94
Wagner W, Ho AD, Zenke M (2010) Different facets of aging in human mesenchymal stem cells. Tissue Eng B Rev 16:445–453
White AD, Swingler RJ, Compston DA (1990) Features of multiple sclerosis in older patients in South Wales. Gerontology 36:159–164
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 176:162–173
Wilson A, Shehadeh LA, Yu H, Webster KA (2010) Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells. BMC Genomics 11:229
Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G 2nd, Roy NS, Goldman SA (2004) Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10:93–97
Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:601–609
Wolswijk G, Noble M (1989) Identification of an adult-specific glial progenitor cell. Development 105:387–400
Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370
Woodbury D, Kathleen R, Ira BB (2002) Adult bone marrow stromal stem cells express germline, ectodermal, endodermal, and mesodermal genes prior to neurogenesis. J Neurosci Res 69:908–917
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 25:216–228
Woodruff RH, Fruttiger M, Richardson WD, Franklin RJM (2004) Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol Cell Neurosci 25:252–262
Yeoh JS, Haan G de (2007) Fibroblast growth factors as regulators of stem cell self-renewal and aging. Mech Ageing Dev 128:17–24
Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761
Zhang J, Li Y, Chen J, Yang M, Katakowski M, Lu M, Chopp M (2004) Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res 1030:19–27
Zhang J, Li Y, Chen J, Cui Y, Lu M, Elias SB, Mitchell JB, Hammill L, Vanguri P, Chopp M (2005) Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 195:16–26
Zhang J, Li Y, Lu M, Cui Y, Chen J, Noffsinger L, Elias SB, Chopp M (2006) Bone marrow stromal cells reduce axonal loss in experimental autoimmune encephalomyelitis mice. J Neurosci Res 84:587–595
Zhang J, Brodie C, Li Y, Zheng X, Roberts C, Lu M, Gao Q, Borneman J, Savant-Bhonsale S, Elias SB, Chopp M (2009) Bone marrow stromal cell therapy reduces proNGF and p75 expression in mice with experimental autoimmune encephalomyelitis. J Neurol Sci 279:30–38
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. Neurobiol Aging 27:1298–1307
Zhou Q, Anderson DJ (2002) The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109:61–73
Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki J (2008) Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7:335–343
Zhou YX, Flint NC, Murtie JC, Le TQ, Armstrong RC (2006) Retroviral lineage analysis of fibroblast growth factor receptor signaling in FGF2 inhibition of oligodendrocyte progenitor differentiation. Glia 54:578–590
Zhu X, Hill RA, Dietrich D, Komitova M, Suzuki R, Nishiyama A (2011) Age-dependent fate and lineage restriction of single NG2 cells. Development 138:745–753
Author information
Authors and Affiliations
Corresponding author
Additional information
Francisco J. Rivera and Patrick Küry are the senior authors and contributed equally to this work.
Rights and permissions
About this article
Cite this article
Jadasz, J.J., Aigner, L., Rivera, F.J. et al. The remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis. Cell Tissue Res 349, 331–347 (2012). https://doi.org/10.1007/s00441-012-1331-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-012-1331-x