Neurochemical Research

, Volume 32, Issue 4–5, pp 783–797 | Cite as

Combination of Growth Factors Enhances Remyelination in a Cuprizone-induced Demyelination Mouse Model

  • Shalini Kumar
  • Juan Carlos Biancotti
  • Masahiro Yamaguchi
  • Jean de Vellis
Original Paper

Abstract

Loss of oligodendrocytes (OLs) is often associated with demyelination. PDGF-AA, bFGF, NT3 and IGF-1 are known to regulate OL proliferation, survival and/or differentiation. Following cuprizone-induced demyelination in mice a combination of above four growth factors (GF) was intracranially injected to stimulate remyelination in vivo. Activation of cell signaling and transcription factors involved in cell proliferation, survival and differentiation was observed in response to GF. Increased cell proliferation and migration occurred in corpus callosum, lateral ventricles, rostral migratory stream and cerebri at 2–5 days post injection (dpi) of GF cocktail. The fate of these newly formed nestin or bromodeoxyuridine (BrdU) positive progenitors was traced to proteoglycan NG2 and glutathione transferase (GST) pi positive cells, early and mature OL lineage markers, respectively. Immunostaining for myelin showed the presence of more myelinated fibers in GF-injected brains at 21 dpi. Remyelination in response to GF was confirmed by electron microscopy. In conclusion, this combination of GF is a promising tool to consider for remyelination strategies.

Keywords

Oligodendrocytes Proliferation Migration Differentiation Myelin Cuprizone Demyelination Remyelination 

References

  1. 1.
    Armstrong RC, Dorn HH, Kufta CV et al (1992) Pre-oligodendrocytes from adult human CNS. J Neurosci 12:1538–1547PubMedGoogle Scholar
  2. 2.
    Chang A, Tourtellotte WW, Rudick R et al (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173PubMedCrossRefGoogle Scholar
  3. 3.
    Goldman JE (2003) What are the characteristics of cycling cells in the adult central nervous system? J Cell Biochem 88:20–23PubMedCrossRefGoogle Scholar
  4. 4.
    Bruck W, Kuhlmann T, Stadelmann C (2003) Remyelination in multiple sclerosis. J Neurol Sci 206:181–185PubMedCrossRefGoogle Scholar
  5. 5.
    Lucchinetti C, Bruck W, Parisi J et al (2000) Heterogeneity of multiple sclerosis lesions:implications for the pathogenesis of demyelination. Ann Neurol 47:707–717PubMedCrossRefGoogle Scholar
  6. 6.
    Prineas JW, Connell F (1979) Remyelination in multiple sclerosis. Ann Neurol 5:22–31PubMedCrossRefGoogle Scholar
  7. 7.
    Raine CS, Wu E (1993) Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52:199–204PubMedCrossRefGoogle Scholar
  8. 8.
    Richardson WD, Smith HK, Sun T et al (2000) Oligodendrocyte lineage and the motor neuron connection. Glia 29:136–142PubMedCrossRefGoogle Scholar
  9. 9.
    Kessaris N, Fogarty M, Iannarelli P et al (2006) Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat Neurosci 9:173–179PubMedCrossRefGoogle Scholar
  10. 10.
    Blakemore WF, Keirstead HS (1999) The origin of remyelinating cells in the central nervous system. J Neuroimmunol 98:69–76PubMedCrossRefGoogle Scholar
  11. 11.
    Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:601–609PubMedGoogle Scholar
  12. 12.
    Noble M, Wolswijk G (1992) Development and regeneration in the O-2A lineage: studies in vitro and in vivo. J Neuroimmunol 40:287–293PubMedCrossRefGoogle Scholar
  13. 13.
    Lee JC, Mayer-Proschel M, Rao MS (2000) Gliogenesis in the central nervous system. Glia 30:105–121PubMedCrossRefGoogle Scholar
  14. 14.
    Aguirre A, Gallo V (2004) Postnatal neurogenesis and gliogenesis in the olfactory bulb from NG2-expressing progenitors of the subventricular zone. J Neurosci 24:10530–10541PubMedCrossRefGoogle Scholar
  15. 15.
    Calver AR, Hall AC, Yu WP et al (1998) Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20:869–882PubMedCrossRefGoogle Scholar
  16. 16.
    Engel U, Wolswijk G (1996) Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells derived from adult rat spinal cord: in vitro characteristics and response to PDGF, bFGF and NT-3. Glia 16:16–26PubMedCrossRefGoogle Scholar
  17. 17.
    McKinnon RD, Smith C, Behar T et al (1993) Distinct effects of bFGF and PDGF on oligodendrocyte progenitor cells. Glia 7:245–254PubMedCrossRefGoogle Scholar
  18. 18.
    Frost EE, Nielsen JA, Le TQ et al (2003) PDGF and FGF2 regulate oligodendrocyte progenitor responses to demyelination. J Neurobiol 54:457–472PubMedCrossRefGoogle Scholar
  19. 19.
    Qian X, Davis AA, Goderie SK et al (1997) FGF2 concentration regulates the generation of neurons and glia from multipotent cortical stem cells. Neuron 18:81–93PubMedCrossRefGoogle Scholar
  20. 20.
    McKinnon RD, Matsui T, Dubois-Dalcq M et al (1990) FGF modulates the PDGF-driven pathway of oligodendrocyte development. Neuron 5:603–614PubMedCrossRefGoogle Scholar
  21. 21.
    Wolswijk G, Noble M (1992) Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J Cell Biol 118:889–900PubMedCrossRefGoogle Scholar
  22. 22.
    Bogler O, Wren D, Barnett SC et al (1990) Cooperation between two growth factors promotes extended self-renewal and inhibits differentiation of oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. Proc Natl Acad Sci USA 87:6368–6372PubMedCrossRefGoogle Scholar
  23. 23.
    Maeda Y, Solanky M, Menonna J et al (2001) Platelet-derived growth factor-alpha receptor-positive oligodendroglia are frequent in multiple sclerosis lesions. Ann Neurol 49:776–785PubMedCrossRefGoogle Scholar
  24. 24.
    Woodruff RH, Fruttiger M, Richardson WD et al (2004) Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol Cell Neurosci 25:252–262PubMedCrossRefGoogle Scholar
  25. 25.
    Murtie JC, Zhou YX, Le TQ et al (2005) PDGF and FGF2 pathways regulate distinct oligodendrocyte lineage responses in experimental demyelination with spontaneous remyelination. Neurobiol Dis 19:171–182PubMedCrossRefGoogle Scholar
  26. 26.
    Kumar S, de Vellis J (1996) Neurotrophin activates signal transduction in oligodendroglial cells: expression of functional TrkC receptor isoforms. J Neurosci Res 44:490–498PubMedCrossRefGoogle Scholar
  27. 27.
    Kumar S, Kahn MA, Dinh L et al (1998) NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo. J Neurosci Res 54:754–765PubMedCrossRefGoogle Scholar
  28. 28.
    Barres BA, Raff MC, Gaese F et al (1994) A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371–375PubMedCrossRefGoogle Scholar
  29. 29.
    Kahn MA, Kumar S, Liebl D et al (1999) Mice lacking NT-3, and its receptor TrkC, exhibit profound deficiencies in CNS glial cells. Glia 26:153–165PubMedCrossRefGoogle Scholar
  30. 30.
    McTigue DM, Horner PJ, Stokes BT et al (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18:5354–5365PubMedGoogle Scholar
  31. 31.
    McMorris FA, Dubois-Dalcq M (1988) Insulin-like growth factor I promotes cell proliferation and oligodendroglial commitment in rat glial progenitor cells developing in vitro. J Neurosci Res 21:199–209PubMedCrossRefGoogle Scholar
  32. 32.
    Ye P, Li L, Richards RG et al (2002) Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 22:6041–6051PubMedGoogle Scholar
  33. 33.
    Barres BA, Schmid R, Sendnter M et al (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295PubMedGoogle Scholar
  34. 34.
    Cho KH, Kim MW, Kim SU (1997) Tissue culture model of Krabbe’s disease: psychosine cytotoxicity in rat oligodendrocyte culture. Dev Neurosci 19:321–327PubMedGoogle Scholar
  35. 35.
    Ye P, D’Ercole AJ (1999) Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. Endocrinology 140:3063–3072PubMedCrossRefGoogle Scholar
  36. 36.
    Mozell RL, McMorris FA (1991) Insulin-like growth factor I stimulates oligodendrocyte development and myelination in rat brain aggregate cultures. J Neurosci Res 30: 382–390PubMedCrossRefGoogle Scholar
  37. 37.
    Werther GA, Russo V, Baker N et al (1998) The role of the insulin-like growth factor system in the developing brain. Horm Res 49(Suppl.1):37–40PubMedCrossRefGoogle Scholar
  38. 38.
    D’Ercole AJ, Ye P, Calikoglu AS et al (1996) The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 13:227–255PubMedGoogle Scholar
  39. 39.
    Liu X, Yao DL, Webster H (1995) Insulin-like growth factor I treatment reduces clinical deficits and lesion severity in acute demyelinating experimental autoimmune encephalomyelitis. Mult Scler 1:2–9PubMedGoogle Scholar
  40. 40.
    Mason JL, Ye P, Suzuki K et al (2000) Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci 20:5703–5708PubMedGoogle Scholar
  41. 41.
    Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316PubMedGoogle Scholar
  42. 42.
    Horbinski C, Chu CT (2005) Kinase signaling cascades in the mitochondrion: a matter of life or death. Free Radic Biol Med 38:2–11PubMedCrossRefGoogle Scholar
  43. 43.
    Kennedy SG, Kandel ES, Cross TK et al (1999) Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 19:5800–5810PubMedGoogle Scholar
  44. 44.
    Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedCrossRefGoogle Scholar
  45. 45.
    Mercurio F, Manning AM (1999) NF-kappaB as a primary regulator of the stress response. Oncogene 18:6163–6171PubMedCrossRefGoogle Scholar
  46. 46.
    Barnes PJ, Adcock IM (1998) Transcription factors and asthma. Eur Respir J 12:221–234PubMedCrossRefGoogle Scholar
  47. 47.
    Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116PubMedCrossRefGoogle Scholar
  48. 48.
    Yamaguchi M, Saito H, Suzuki M et al (2000) Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 11:1991–1996PubMedCrossRefGoogle Scholar
  49. 49.
    Filippov V, Kronenberg G, Pivneva T et al (2003) Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol Cell Neurosci 23:373–382PubMedCrossRefGoogle Scholar
  50. 50.
    Tansey FA, Cammer W (1991) A pi form of glutathione-S-transferase is a myelin- and oligodendrocyte-associated enzyme in mouse brain. J Neurochem 57:95–102PubMedCrossRefGoogle Scholar
  51. 51.
    Jurevics H, Largent C, Hostettler J et al (2002) Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J Neurochem 82:126–136PubMedCrossRefGoogle Scholar
  52. 52.
    Fukunaga K, Ishigami T, Kawano T, (2005) Transcriptional regulation of neuronal genes and its effect on neural functions: Expression and function of forkhead transcription factors in neurons. J Pharmacol Sci 98:205–211PubMedCrossRefGoogle Scholar
  53. 53.
    Gan L, Zheng W, Chabot J-G, Unterman TG, Quirion R (2005) Nuclear/cytoplasmic shuttling of the transcription factor FOXO1 is regulated by neurotrophic factors. J Neurochem 93:1209–1219PubMedCrossRefGoogle Scholar
  54. 54.
    Johnson JR, Chu AK, Sato-Bigbee C, (2000) Possible role of CREB in the stimulation of oligodendrocytes precursor cell proliferation by neurotrophin-3. J Neurochem 74:1409–1417PubMedCrossRefGoogle Scholar
  55. 55.
    Hu X, Jin L, Feng L (2004) Erk1/2 but not PI3K pathway is required for neurotrophin 3-induced oligodendrocyte differentiation of post-natal neural stem cells. J Neurochem 90:1339–1347PubMedCrossRefGoogle Scholar
  56. 56.
    Arnett HA, Fancy SP, Alberta JA et al (2004) bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306:2111–2115PubMedCrossRefGoogle Scholar
  57. 57.
    McKinnon RD, Waldron S, Kiel ME (2005) PDGF alpha-receptor signal strength controls an RTK rheostat that integrates phosphoinositol 3′-kinase and phospholipase Cgamma pathways during oligodendrocyte maturation. J Neurosci 25:3499–3508PubMedCrossRefGoogle Scholar
  58. 58.
    Stariha RL, Kim SU (2001) Protein kinase C and mitogen-activated protein kinase signalling in oligodendrocytes. Microsc Res Tech 52:680–688PubMedCrossRefGoogle Scholar
  59. 59.
    Oppenheim RW (1991) Cell death during development of the nervous system. Annual Rev Neurosci 14:453–501CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Shalini Kumar
    • 1
  • Juan Carlos Biancotti
    • 1
  • Masahiro Yamaguchi
    • 2
  • Jean de Vellis
    • 1
  1. 1.Departments of Neurobiology and PsychiatryMental Retardation Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of CaliforniaLos AngelesUSA
  2. 2.Department of PhysiologyUniversity of TokyoTokyoJapan

Personalised recommendations