Neurochemical Research

, Volume 32, Issue 2, pp 263–271 | Cite as

CNTF-Activated Astrocytes Release a Soluble Trophic Activity for Oligodendrocyte Progenitors

  • Phillip J. Albrecht
  • Jonathan C. Enterline
  • Jason Cromer
  • Steven W. Levison


CNTF (ciliary neurotrophic factor) has been suggested to be an important survival factor for oligodendrocytes; however, this effect is inconsistently obtained and myelination appears normal in CNTF null animals. On the other hand, CNTF stimulates astrocytes to produce growth and trophic factors. Therefore, we tested the hypothesis that CNTF acts indirectly through astrocytes to promote oligodendrocyte survival. We show that CNTF-stimulated astrocytes release a trophic factor(s) that leads to more than double the number of oligodendrocyte progenitor cells (OPCs) by 48 h. The trophic activity fractionates at greater than 30 kD. By contrast, OPCs grown in CNTF supplemented chemically defined medium fared no better than cells grown without CNTF. Untreated astrocytes, and CNTF- and IL-1β -stimulated astrocytes all promoted the proliferation of OPCs to a similar extent, but only the CNTF-stimulated astrocyte conditioned media (CM) resulted in increased OPCs numbers. Cumulatively, these results confirm previous data indicating that astrocytes release potent mitogens for oligodendroglia, and demonstrate that CNTF stimulates astrocytes to release an OPC survival-promoting activity.

Key words

Ciliary neurotrophic factor Regeneration Trophic factors Myelin Remyelination 



We thank Dr. Terri Wood for her help with the experiments and her constructive comments on this manuscript. This work was supported by a grant to SWL from the National Multiple Sclerosis Society, RG-2829.


  1. 1.
    Ness JK, Mitchell NE, Wood TL (2002) IGF-I and NT-3 signaling pathways in developing oligodendrocytes: differential regulation and activation of receptors and the downstream effector Akt. Dev Neurosci 24(5):437–445PubMedCrossRefGoogle Scholar
  2. 2.
    Canoll PD, et al. (1996) GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 17:229–243PubMedCrossRefGoogle Scholar
  3. 3.
    Gard AL, et al. (1995) Astroglial control of oligodendrocyte survival mediated by PDGF and leukemia inhibitory factor-like protein. Development 121:2187–2197PubMedGoogle Scholar
  4. 4.
    Grinspan JB, Franceschini B (1995) Platelet-derived growth factor is a survival factor for PSA-NCAM + oligodendrocyte pre-progenitor cells. J Neurosci Res 41:540–551PubMedCrossRefGoogle Scholar
  5. 5.
    Barres BA, et al. (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46PubMedCrossRefGoogle Scholar
  6. 6.
    Cui QL, Fogle E, Almazan G (2006) Muscarinic acetylcholine receptors mediate oligodendrocyte progenitor survival through Src-like tyrosine kinases and PI3K/Akt pathways. Neurochem Int 48(5):383–393PubMedCrossRefGoogle Scholar
  7. 7.
    Li W, et al. (2004) Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56(6):767–77PubMedCrossRefGoogle Scholar
  8. 8.
    Sattler MB, et al. (2004) Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 11(Suppl 2):S181–192PubMedCrossRefGoogle Scholar
  9. 9.
    Colognato H, et al. (2004) Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development. J Cell Biol 167(2):365–375PubMedCrossRefGoogle Scholar
  10. 10.
    Molina-Holgado E, et al. (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22(22):9742–9753PubMedGoogle Scholar
  11. 11.
    Jaillard C, et al. (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 25(6):1459–1469PubMedCrossRefGoogle Scholar
  12. 12.
    Shankar SL, et al, (2003) The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci 23(10):4208–4218PubMedGoogle Scholar
  13. 13.
    Saini HS, et al. (2005) Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J. Neurochem 95(5):1298–1310PubMedCrossRefGoogle Scholar
  14. 14.
    2Nait-Oumesmar B, et al. (1999) Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci 11(12):4357–4366CrossRefGoogle Scholar
  15. 15.
    Vemuri GS, McMorris FA (1996) Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. Development 122:2529–2537PubMedGoogle Scholar
  16. 16.
    Ness JK, Scaduto RC, Wood TL (2004) IGF-I prevents glutamate-mediated Bax translocation and cytochrome C release in O4 oligodendrocyte progenitors. Glia 46:183–194PubMedCrossRefGoogle Scholar
  17. 17.
    Ness JK, Wood TL (2002) Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis. Mol Cell Neurosci 20(3):476–488PubMedCrossRefGoogle Scholar
  18. 18.
    Barres BA, et al. (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295PubMedGoogle Scholar
  19. 19.
    Barres BA, et al. (1994) A crucial role for neurotrophin-3 in oligodendrocyte development. Nature 367:371–375PubMedCrossRefGoogle Scholar
  20. 20.
    Louis JC, et al. (1993) CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689–692PubMedCrossRefGoogle Scholar
  21. 21.
    Mayer M, Bhakoo K, Noble M (1994) Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development 120:143–153PubMedGoogle Scholar
  22. 22.
    Kahn MA, de Vellis J (1994) Regulation of an oligodendrocyte progenitor cell line by the interleukin-6 family of cytokines. Glia 12:87–98PubMedCrossRefGoogle Scholar
  23. 23.
    Barres BA, et al. (1996) Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol Cell Neurosci 8(2/3):146–156CrossRefGoogle Scholar
  24. 24.
    D’Souza SD, Alinauskas KA Antel JP (1996) Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. J Neurosci Res 43(3):289–298PubMedCrossRefGoogle Scholar
  25. 25.
    DeChiara TM, et al. (1995) Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 83:313–322PubMedCrossRefGoogle Scholar
  26. 26.
    Sendtner M, et al. (1994) Ciliary neurotrophic factor. J Neurobiol 25(11):1436–1453PubMedCrossRefGoogle Scholar
  27. 27.
    Albrecht PJ, et al. (2002) Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol 173(1):46–62PubMedCrossRefGoogle Scholar
  28. 28.
    Levison SW, McCarthy KD (1991) Astroglia in culture. In Banker GA, Goslin K (Eds) Culturing nerve cells. MIT press, Cambridge, p 309–336Google Scholar
  29. 29.
    Young GM, Levison SW (1997) An improved method for propagating oligodendrocyte progenitors in vitro. J Neurosci Meth 77:163–168CrossRefGoogle Scholar
  30. 30.
    Jiang F-J, Levison SW, Wood TL (1999) Ciliary neurotrophic factor induces expression of the IGF type 1 receptor and FGF receptor 1 mRNAs in adult rat brain oligodendrocytes. J Neurosci Res 57:447–457PubMedCrossRefGoogle Scholar
  31. 31.
    Levison SW, et al. (2000) IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 32(3):328–337PubMedCrossRefGoogle Scholar
  32. 32.
    Albrecht PJ, et al. (2003) Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiol Dis 13(2):89–101PubMedCrossRefGoogle Scholar
  33. 33.
    Noble M, Murray K (1984) Purified astrocytes promote the in vitro division of a bipotential glial progenitor cell. EMBO J 3:2243–2247 PubMedGoogle Scholar
  34. 34.
    Liberto CM, et al. (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89(5):1092–1100PubMedCrossRefGoogle Scholar
  35. 35.
    Grinspan JB, et al. (1993) Trophic effects of basic fibroblast growth factor (bFGF) on differentiated oligodendroglia: a mechanism for regeneration of the oligodendroglial lineage. J Neurosci Res 36(6):672–680PubMedCrossRefGoogle Scholar
  36. 36.
    Cohen RI, et al. (1996) Nerve growth factor and neurotrophin-3 differentially regulate the proliferation and survival of developing rat brain oligodendrocytes. J Neurosci 16(20):6433–6442PubMedGoogle Scholar
  37. 37.
    Richardson WD, et al. (1988) A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53:309–319PubMedCrossRefGoogle Scholar
  38. 38.
    Pinkas-Kramarski R, et al. (1994) Brain neurons and glial cells express Neu differentiation factor/heregulin: a survival factor for astrocytes. Proc Natl Acad Sci USA 91(20):9387–9391PubMedCrossRefGoogle Scholar
  39. 39.
    Gensert JM, Goldman JE (1997) Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19(1):197–203PubMedCrossRefGoogle Scholar
  40. 40.
    Redwine JM, Armstrong RC (1998) In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination. J Neurobiol 37(3):413–428PubMedCrossRefGoogle Scholar
  41. 41.
    Prineas JW, et al. (1993) Multiple sclerosis: Remyelination of nascent lesions. Ann Neurol 33:137–151PubMedCrossRefGoogle Scholar
  42. 42.
    Wolswijk G (2002) Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125(Pt 2):338–349PubMedCrossRefGoogle Scholar
  43. 43.
    Chang A, et al. (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346(3):165–173PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Phillip J. Albrecht
    • 1
  • Jonathan C. Enterline
    • 2
  • Jason Cromer
    • 3
  • Steven W. Levison
    • 4
  1. 1.Center for Neuropharmacolgy and NeuroscienceAlbany Medical CenterAlbanyUSA
  2. 2.Pennsylvania State University College of MedicineHersheyUSA
  3. 3.Graduate Program in NeuroscienceUniversity of Connecticut Health CenterFarmingtonUSA
  4. 4.Department of Neurology and NeuroscienceUMDNJ-New Jersey Medical SchoolEast Orange, NewarkUSA

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