Abstract
In multiple sclerosis, the central nervous system is lesioned through invasion of plaque‐forming inflammatory cells, primarily contributing to immune attack of myelin and oligodendrocytes. In this report we address the possible activation and differentiation of central nervous system stem cells following such immunological insults in a well‐characterized rat model of multiple sclerosis characterised by spinal cord pathology. Dye‐labeled central nervous system stem cells, residing within the ependymal layer of the central canal responded to the multiple sclerosis‐like conditions by proliferation, while some of the migrating stem cell‐derived cells expressed markers typical for oligodendrocytes (O4) and astrocytes (glial fibrillary acidic protein, GFAP) in the demyelinated area. Our results indicate that regenerative stem cell activation following immunoactivity is different from that after trauma, exemplified by the slower time course of stem cell proliferation and migration of progeny, in addition to the ability of the stem cell‐derived cells to express oligodendrocyte markers. Finally, deleterious effects of macrophages on the stem cell population were evident and may contribute to the depletion of the stem cell population in neuroinflammatory disorders.
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References
- 1. 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. [DOI] [PubMed] [Google Scholar]
- 2. Brosnan CF, Battistini L, Raine CS, Dickson DW, Casadevall A, Lee SC (1994) Reactive nitrogen intermediates in human neuropathology: an overview. Dev Neurosci 16:152–161. [DOI] [PubMed] [Google Scholar]
- 3. Brundin L, Morcos E, Olsson T, Wiklund NP, Andersson M (1999) Increased intrathecal nitric oxide formation in multiple sclerosis; cerebrospinal fluid nitrite as activity marker. Eur J Neurol 6:585–590. [DOI] [PubMed] [Google Scholar]
- 4. Bulte JW, Zhang S, van Gelderen P, Herynek V, Jordan EK, Duncan ID, Frank JA (1999) Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. Proc Natl Acad Sci U S A 96:15256–15261. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Di Bello IC, Dawson MR, Levine JM, Reynolds R (1999) Generation of oligodendroglial progenitors in acute inflammatory demyelinating lesions of the rat brain stem is associated with demyelination rather than inflammation. J Neurocytol 28:365–381. [DOI] [PubMed] [Google Scholar]
- 6. 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. J Neurosci 20:2218–2228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Johansson C, Svensson M, Wallstedt L, Janson A, Frisen J (1999) Neural stem cells in the adult human brain. Experimental Cell Research 253:733–736. [DOI] [PubMed] [Google Scholar]
- 8. Johansson CB. (2002) Isolation and characterization of adult neural stem cells. Thesis. Department of Cell‐ and Molecular Biology. Karolinska Institutet, Stockholm, Sweden.
- 9. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisen J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96:25–34. [DOI] [PubMed] [Google Scholar]
- 10. Keirstead HS, Blakemore WF (1997) Identification of post‐mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J Neuropathol Exp Neurol 56:1191–1201. [DOI] [PubMed] [Google Scholar]
- 11. Kojima A, Tator CH (2002) Intrathecal administration of epidermal growth factor and fibroblast growth factor 2 promotes ependymal proliferation and functional recovery after spinal cord injury in adult rats. J Neurotrauma 19:223–238. [DOI] [PubMed] [Google Scholar]
- 12. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Lassman H (1983) Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis., pp. 37–72. In Springer Verlag, New York . [PubMed] [Google Scholar]
- 14. Liu K, Wang Z, Wang H, Zhang Y (2002) Nestin expression and proliferation of ependymal cells in adult rat spinal cord after injury. Chin Med J (Engl) 115:339–341. [PubMed] [Google Scholar]
- 15. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717. [DOI] [PubMed] [Google Scholar]
- 16. Marburg O (1906) Die sogenannte ‘akute Multiple Sklerose. Jahrb Psychiatrie 27:211–312. [Google Scholar]
- 17. 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. [DOI] [PubMed] [Google Scholar]
- 18. 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 U S A 99:13211–13216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer L, Cho ES (1993) Multiple sclerosis. Pathology of recurrent lesions. Brain 116:681–693. [DOI] [PubMed] [Google Scholar]
- 20. Prineas JW, Kwon EE, Goldenberg PZ, Ilyas AA, Quarles RH, Benjamins JA, Sprinkle TJ (1989) Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest 61:489–503. [PubMed] [Google Scholar]
- 21. Raine CS, Wu E (1993) Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52:199–204. [PubMed] [Google Scholar]
- 22. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710. [DOI] [PubMed] [Google Scholar]
- 23. Ruffini F, Furlan R, Poliani PL, Brambilla E, Marconi PC, Bergami A, Desina G, Glorioso JC, Comi G, Martino G (2001) Fibroblast growth factor‐II gene therapy reverts the clinical course and the pathological signs of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice. Gene Ther 8:1207–1213. [DOI] [PubMed] [Google Scholar]
- 24. Storch MK, Stefferl A, Brehm U, Weissert R, Wallstrom E, Kerschensteiner M, Olsson T, Linington C, Lassmann H (1998) Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8:681–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Temple S, Alvarez‐Buylla A (1999) Stem cells in the adult mammalian central nervous system. Curr Opin Neurobiol 9:135–141. [DOI] [PubMed] [Google Scholar]
- 26. Weissert R, Wallstrom E, Storch MK, Stefferl A, Lorentzen J, Lassmann H, Linington C, Olsson T (1998) MHC haplotype‐dependent regulation of MOG‐induced EAE in rats. J Clin Invest 102:1265–1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Wolswijk G (2002) Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125:338–349. [DOI] [PubMed] [Google Scholar]
- 28. Zhang F, Clarke J, Ferretti P (2000) FGF‐2 Up‐regulation and proliferation of neural progenitors in the regenerating amphibian spinal cord in vivo. Dev Biol 225:381–391. [DOI] [PubMed] [Google Scholar]