Abstract
Acute demyelination of adult CNS, resulting from trauma or disease, is initially followed by remyelination. However, chronic lesions with subsequent functional impairment result from eventual failure of the remyelination process, as seen in multiple sclerosis. Studies using animal models of successful remyelination delineate a progression of events facilitating remyelination. A universal feature of this repair process is extensive proliferation of oligodendrocyte progenitor cells (OPs) in response to demyelination. To investigate signals that regulate OP proliferation in response to demyelination we used murine hepatitis virus‐A59 (MHV‐A59) infection of adult mice to induce focal demyelination throughout the spinal cord followed by spontaneous remyelination. We cultured glial cells directly from demyelinating and remyelinating spinal cords using conditions that maintain the dramatically enhanced OP proliferative response prior to CNS remyelination. We identify PDGF and FGF2 as significant mitogens regulating this proliferative response. Furthermore, we demonstrate endogenous PDGF and FGF2 activity in these glial cultures isolated from demyelinated CNS tissue. These findings correlate well with our previous demonstration of increased in vivo expression of PDGF and FGF2 ligand and corresponding receptors in MHV‐A59 lesions. Together these studies support the potential of these pathways to function in vivo as critical factors in regulating remyelination. © 2003 Wiley Periodicals, Inc. J Neurobiol 54: 457–472, 2003
Keywords: PDGF, FGF2, remyelination, oligodendrocyte progenitor, demyelinating disease
This article is a US Government work and, as such, is in the public domain in the United States of America.
REFERENCES
- Armstrong R, Friedrich VL Jr, Holmes KV, Dubois‐Dalcq M. 1990. In vitro analysis of the oligodendrocyte lineage in mice during demyelination and remyelination. J Cell Biol 111: 1183–1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong RC. 1998. Isolation and characterization of immature oligodendrocyte lineage cells. Methods 16: 282–292. [DOI] [PubMed] [Google Scholar]
- Armstrong RC. 2000. Potential Roles of Trophic Factors in CNS Development and Recovery from Demyelinating Disease In: Mocchetti I, editor. Neurobiology of the Trophins. Johnson City, TN: FP Graham Publishing Co; p 333–353. [Google Scholar]
- Armstrong RC, Dorn HH, Kufta CV, Friedman E, Dubois‐Dalcq ME. 1992. Pre‐oligodendrocytes from adult human CNS. J Neurosci 12: 1538–1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP. 2001. TNFalpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4: 1116–1122. [DOI] [PubMed] [Google Scholar]
- Banai S, Wolf Y, Golomb G, Pearle A, Waltenberger J, Fishbein I, Schneider A, Gazit A, Perez L, Huber R, Lazarovichi G, Rabinovich L, Levitzki A, Gertz SD. 1998. PDGF‐receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine. Circulation 97: 1960–1969. [DOI] [PubMed] [Google Scholar]
- Bansal R, Kumar M, Murray K, Morrison RS, Pfeiffer SE. 1996. Regulation of FGF receptors in the oligodendrocyte lineage. Mol Cell Neurosci 7: 263–275. [DOI] [PubMed] [Google Scholar]
- Bansal R, Pfeiffer SE. 1992. Novel stage in the oligodendrocyte lineage defined by reactivity of progenitors with R‐mAb prior to O1 anti‐galactocerebroside. J Neurosci Res 32: 309–316. [DOI] [PubMed] [Google Scholar]
- Baron W, Metz B, Bansal R, Hoekstra D, de Vries H. 2000. PDGF and FGF‐2 signaling in oligodendrocyte progenitor cells: regulation of proliferation and differentiation by multiple intracellular signaling pathways. Mol Cell Neurosci 15: 314–329. [DOI] [PubMed] [Google Scholar]
- Bögler O, Wren D, Barnett SC, Land H, Noble M. 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: 6368–6372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bottenstein JE, Sato GH. 1979. Growth of a rat neuroblastoma cell line in serum‐free supplemented medium. Proc Natl Acad Sci USA 76: 514–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cannella B, Hoban CJ, Gao YL, Garcia‐Arenas R, Lawson D, Marchionni M, Gwynne D, Raine CS. 1998. The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. Proc Natl Acad Sci USA 95: 10100–10105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carroll WM, Jennings AR, Ironside LJ. 1998. Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination. Brain 121: 293–302. [DOI] [PubMed] [Google Scholar]
- 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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: 16–26. [DOI] [PubMed] [Google Scholar]
- ffrench‐Constant C, Raff MC. 1986. The oligodendrocyte‐type‐2 astrocyte cell lineage is specialized for myelination. Nature 323: 335–338. [DOI] [PubMed] [Google Scholar]
- Gensert JM, Goldman JE. 1997. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19: 197–203. [DOI] [PubMed] [Google Scholar]
- Goddard DR, Berry M, Butt AM. 1999. In vivo actions of fibroblast growth factor‐2 and insulin‐like growth factor‐I on oligodendrocyte development and myelination in the central nervous system. J Neurosci Res 57: 74–85. [DOI] [PubMed] [Google Scholar]
- Godfraind C, Friedrich VL, Holmes KV, Dubois‐Dalcq M. 1989. In vivo analysis of glial cell phenotypes during a viral demyelinating disease in mice. J Cell Biol 109: 2405–2416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grinspan JB, Reeves MF, Coulaloglou MJ, Nathanson D, Pleasure D. 1996. Re‐entry into the cell cycle is required for bFGF‐induced oligodendroglial dedifferentiation and survival. J Neurosci Res 46: 456–464. [DOI] [PubMed] [Google Scholar]
- Hajihosseini M, Iavachev L, Price J. 1993. Evidence that retroviruses integrate into post‐replication host DNA. Embo J 12: 4969–4974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hart IK, Richardson WD, Heldin CH, Westermark B, Raff MC. 1989. PDGF receptors on cells of the oligodendrocyte‐type‐2 astrocyte (O‐2A) cell lineage. Development 105: 595–603. [DOI] [PubMed] [Google Scholar]
- Hebert JM, Basilico C, Goldfarb M, Haub O, Martin GR. 1990. Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Dev Biol 138: 454–463. [DOI] [PubMed] [Google Scholar]
- Heldin CH, Westermark B. 1999. Mechanism of action and in vivo role of platelet‐derived growth factor. Physiol Rev 79: 1283–1316. [DOI] [PubMed] [Google Scholar]
- Hinks GL, Franklin RJ. 1999. Distinctive patterns of PDGF‐A, FGF‐2, IGF‐I, and TGF‐beta1 gene expression during remyelination of experimentally‐induced spinal cord demyelination. Mol Cell Neurosci 14: 153–168. [DOI] [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. J Neurosci 20: 2218–2228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hudson LD, Berndt JA, Puckett C, Kozak CA, Lazzarini RA. 1987. Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proc Natl Acad Sci USA 84: 1454–1458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iwamoto H, Nakamuta M, Tada S, Sugimoto R, Enjoji M, Nawata H. 2000. Platelet‐derived growth factor receptor tyrosine kinase inhibitor AG1295 attenuates rat hepatic stellate cell growth. J Lab Clin Med 135: 406–412. [DOI] [PubMed] [Google Scholar]
- Jordan CA, Friedrich VL Jr, Godfraind C, Cardellechio CB, Holmes KV, Dubois‐Dalcq M. 1989. Expression of viral and myelin gene transcripts in a murine CNS demyelinating disease caused by a coronavirus. Glia 2: 318–329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. [PubMed] [Google Scholar]
- Kovalenko M, Gazit A, Bohmer A, Rorsman C, Ronnstrand L, Heldin CH, Waltenberger J, Bohmer FD, Levitzki A. 1994. Selective platelet‐derived growth factor receptor kinase blockers reverse sis‐transformation. Cancer Res 54: 6106–6114. [PubMed] [Google Scholar]
- Levison SW, Young GM, Goldman JE. 1999. Cycling cells in the adult rat neocortex preferentially generate oligodendroglia. J Neurosci Res 57: 435–446. [PubMed] [Google Scholar]
- Liu HN, Larocca JN, Almazan G. 1999. Molecular pathways mediating activation by kainate of mitogen‐activated protein kinase in oligodendrocyte progenitors. Brain Res Mol Brain Res 66: 50–61. [DOI] [PubMed] [Google Scholar]
- Liu X, Mashour GA, Webster HF, Kurtz A. 1998. Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: temporally distinct expression of midkine and pleiotrophin. Glia 24: 390–397. [DOI] [PubMed] [Google Scholar]
- Ludwin SK. 1979. An autoradiographic study of cellular proliferation in remyelination of the central nervous system. Am J Pathol 95: 683–696. [PMC free article] [PubMed] [Google Scholar]
- Maeda Y, Solanky M, Menonna J, Chapin J, Li W, Dowling P. 2001. Platelet‐derived growth factor‐alpha receptor‐positive oligodendroglia are frequent in multiple sclerosis lesions. Ann Neurol 49: 776–785. [DOI] [PubMed] [Google Scholar]
- Mason JL, Goldman JE. 2002. A2B5(+) and O4(+) Cycling Progenitors in the Adult Forebrain White Matter Respond Differentially to PDGF‐AA, FGF‐2, and IGF‐1. Mol Cell Neurosci 20: 30–42. [DOI] [PubMed] [Google Scholar]
- Mason JL, Jones JJ, Taniike M, Morell P, Suzuki K, Matsushima GK. 2000. Mature oligodendrocyte apoptosis precedes IGF‐1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination/remyelination. J Neurosci Res 61: 251–262. [DOI] [PubMed] [Google Scholar]
- McKinnon RD, Matsui T, Dubois‐Dalcq M, Aaronson SA. 1990. FGF modulates the PDGF‐driven pathway of oligodendrocyte development. Neuron 5: 603–614. [DOI] [PubMed] [Google Scholar]
- McKinnon RD, Piras G, Ida JA Jr, Dubois‐Dalcq M. 1993. A role for TGF‐beta in oligodendrocyte differentiation. J Cell Biol 121: 1397–1407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McTigue DM, Wei P, Stokes BT. 2001. Proliferation of NG2‐positive cells and altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci 21: 3392–3400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mercola M, Wang CY, Kelly J, Brownlee C, Jackson‐Grusby L, Stiles C, Bowen‐Pope D. 1990. Selective expression of PDGF A and its receptor during early mouse embryogenesis. Dev Biol 138: 114–122. [DOI] [PubMed] [Google Scholar]
- Messersmith DJ, Murtie JC, Le TQ, Frost EE, Armstrong RC. 2000. Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. J Neurosci Res 62: 241–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nilsson E, Parrott JA, Skinner MK. 2001. Basic fibroblast growth factor induces primordial follicle development and initiates folliculogenesis. Mol Cell Endocrinol 175: 123–130. [DOI] [PubMed] [Google Scholar]
- Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB. 1996a. Co‐localization of NG2 proteoglycan and PDGF alpha‐receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res 43: 299–314. [DOI] [PubMed] [Google Scholar]
- Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB. 1996b. Interaction between NG2 proteoglycan and PDGF alpha‐receptor on O2A progenitor cells is required for optimal response to PDGF. J Neurosci Res 43: 315–330. [DOI] [PubMed] [Google Scholar]
- Ornitz DM, Itoh N. 2001. Fibroblast growth factors. Genome Biol 2: reviews3005 1–3005.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. 1996. Receptor specificity of the fibroblast growth factor family. J Biol Chem 271: 15292–15297. [DOI] [PubMed] [Google Scholar]
- Price J, Turner D, Cepko C. 1987. Lineage analysis in the vertebrate nervous system by retrovirus‐mediated gene transfer. Proc Natl Acad Sci USA 84: 156–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES. 1993. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33: 137–151. [DOI] [PubMed] [Google Scholar]
- Pringle NP, Mudhar HS, Collarini EJ, Richardson WD. 1992. PDGF receptors in the rat CNS: during late neurogenesis, PDGF alpha‐receptor expression appears to be restricted to glial cells of the oligodendrocyte lineage. Development 115: 535–551. [DOI] [PubMed] [Google Scholar]
- Raine CS, Wu E. 1993. Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol 52: 199–204. [PubMed] [Google Scholar]
- Redwine JM, Armstrong RC. 1998. In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination. J Neurobiol 37: 413–428. [DOI] [PubMed] [Google Scholar]
- Reynolds R, Cenci di Bello I, Dawson M, Levine J. 2001. The response of adult oligodendrocyte progenitors to demyelination in EAE. Prog Brain Res 132: 165–174. [DOI] [PubMed] [Google Scholar]
- Roy NS, Wang S, Harrison‐Restelli C, Benraiss A, Fraser RA, Gravel M, Braun PE, Goldman SA. 1999. Identification, isolation, and promoter‐defined separation of mitotic oligodendrocyte progenitor cells from the adult human subcortical white matter. J Neurosci 19: 9986–9995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scolding NJ, Rayner PJ, Sussman J, Shaw C, Compston DA. 1995. A proliferative adult human oligodendrocyte progenitor. NeuroReport 6: 441–445. [DOI] [PubMed] [Google Scholar]
- Shi J, Marinovich A, Barres BA. 1998. Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J Neurosci 18: 4627–4636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van Heyningen P, Calver AR, Richardson WD. 2001. Control of progenitor cell number by mitogen supply and demand. Curr Biol 11: 232–241. [DOI] [PubMed] [Google Scholar]
- Wolswijk G, Noble M. 1989. Identification of an adult‐specific glial progenitor cell. Development 105: 387–400. [DOI] [PubMed] [Google Scholar]
- 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: 889–900. [DOI] [PMC free article] [PubMed] [Google Scholar]