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Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation

Nature Medicine volume 11, pages 966–972 (2005)Cite this article

Abstract

Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.

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Figure 1: Hyaluronan accumulates in demyelinated lesions of individuals with multiple sclerosis and mice with EAE.
Figure 2: Hyaluronan accumulates in the white matter of transgenic mice that express CD44 under the control of a myelin-specific promoter.
Figure 3: HMW hyaluronan prevents remyelination of lysolecithin-induced lesions.
Figure 4: Accumulation of OPCs in demyelinated lysolecithin lesions in the presence of HMW hyaluronan.
Figure 5: HMW hyaluronan inhibits OPC maturation.
Figure 6: Removing hyaluronan from oligodendrocyte progenitor cultures promotes OPC maturation.

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References

  1. Lassmann, H. Classification of demyelinating diseases at the interface between etiology and pathogenesis. Curr. Opin. Neurol. 14, 253–258 (2001).

    Article  CAS  Google Scholar 

  2. De Groot, C.J. & Woodroofe, M.N. The role of chemokines and chemokine receptors in CNS inflammation. Prog. Brain Res. 132, 533–544 (2001).

    Article  CAS  Google Scholar 

  3. Wolswijk, G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125, 338–349 (2002).

    Article  Google Scholar 

  4. Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B.D. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

    Article  CAS  Google Scholar 

  5. Chang, A., Tourtellotte, W.W., Rudick, R. & Trapp, B.D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    Article  Google Scholar 

  6. Wolswijk, G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci. 18, 601–609 (1998).

    Article  CAS  Google Scholar 

  7. Scolding, N. et al. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121, 2221–2228 (1998).

    Article  Google Scholar 

  8. Maeda, Y. et al. Platelet-derived growth factor-alpha receptor-positive oligodendroglia are frequent in multiple sclerosis lesions. Ann. Neurol. 49, 776–785 (2001).

    Article  CAS  Google Scholar 

  9. Toole, B.P. Hyaluronan: from extracellular glue to pericellular cue. Nat. Rev. Cancer 4, 528–539 (2004).

    Article  CAS  Google Scholar 

  10. Weigel, P.H., Fuller, G.M. & LeBoeuf, R.D. A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing. J. Theor. Biol. 119, 219–234 (1986).

    Article  CAS  Google Scholar 

  11. Sampson, P.M., Rochester, C.L., Freundlich, B. & Elias, J.A. Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase. J. Clin. Invest. 90, 1492–1503 (1992).

    Article  CAS  Google Scholar 

  12. Moseley, R., Waddington, R.J. & Embery, G. Degradation of glycosaminoglycans by reactive oxygen species derived from stimulated polymorphonuclear leukocytes. Biochim. Biophys. Acta 1362, 221–231 (1997).

    Article  CAS  Google Scholar 

  13. Agren, U.M., Tammi, R.H. & Tammi, M.I. Reactive oxygen species contribute to epidermal hyaluronan catabolism in human skin organ culture. Free Radic. Biol. Med. 23, 996–1001 (1997).

    Article  CAS  Google Scholar 

  14. Marret, S. et al. Expression and effects of hyaluronan and of the hyaluronan-binding protein hyaluronectin in newborn rat brain glial cell cultures. J. Neurochem. 62, 1285–1295 (1994).

    Article  CAS  Google Scholar 

  15. Ponta, H., Sherman, L. & Herrlich, P.A. CD44: from adhesion molecules to signalling regulators. Nat. Rev. Mol. Cell Biol. 4, 33–45 (2003).

    Article  CAS  Google Scholar 

  16. Jiang, H. et al. A requirement for the CD44 cytoplasmic domain for hyaluronan binding, pericellular matrix assembly, and receptor-mediated endocytosis in COS-7 cells. J. Biol. Chem. 277, 10531–10538 (2002).

    Article  CAS  Google Scholar 

  17. Moretto, G., Xu, R.Y. & Kim, S.U. CD44 expression in human astrocytes and oligodendrocytes in culture. J. Neuropathol. Exp. Neurol. 52, 419–423 (1993).

    Article  CAS  Google Scholar 

  18. Vogel, H., Butcher, E.C. & Picker, L.J. H-CAM expression in the human nervous system: evidence for a role in diverse glial interactions. J. Neurocytol. 21, 363–373 (1992).

    Article  CAS  Google Scholar 

  19. Liu, Y. et al. Oligodendrocyte and astrocyte development in rodents: an in situ and immunohistological analysis during embryonic development. Glia 40, 25–43 (2002).

    Article  Google Scholar 

  20. Alfei, L. et al. Hyaluronate receptor CD44 is expressed by astrocytes in the adult chicken and in astrocyte cell precursors in early development of the chick spinal cord. Eur. J. Histochem. 43, 29–38 (1999).

    CAS  PubMed  Google Scholar 

  21. Akiyama, H., Tooyama, I., Kawamata, T., Ikeda, K. & McGeer, P.L. Morphological diversities of CD44 positive astrocytes in the cerebral cortex of normal subjects and patients with Alzheimer's disease. Brain Res. 632, 249–259 (1993).

    Article  CAS  Google Scholar 

  22. Girgrah, N. et al. Localization of the CD44 glycoprotein to fibrous astrocytes in normal white matter and to reactive astrocytes in active lesions in multiple sclerosis. J. Neuropathol. Exp. Neurol. 50, 779–792 (1991).

    Article  CAS  Google Scholar 

  23. Ito, M. et al. Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J. Neuropathol. Exp. Neurol. 60, 1004–1019 (2001).

    Article  CAS  Google Scholar 

  24. Bouvier-Labit, C., Liprandi, A., Monti, G., Pellissier, J.F. & Figarella-Branger, D. CD44H is expressed by cells of the oligodendrocyte lineage and by oligodendrogliomas in humans. J. Neurooncol. 60, 127–134 (2002).

    Article  Google Scholar 

  25. Haegel, H., Tolg, C., Hofmann, M. & Ceredig, R. Activated mouse astrocytes and T cells express similar CD44 variants. Role of CD44 in astrocyte/T cell binding. J. Cell Biol. 122, 1067–1077 (1993).

    Article  CAS  Google Scholar 

  26. Struve, J. et al. Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation. Glia (in the press).

  27. Tuohy, T.M. et al. CD44 overexpression by oligodendrocytes: a novel mouse model of inflammation-independent demyelination and dysmyelination. Glia 47, 335–345 (2004).

    Article  Google Scholar 

  28. Mummert, M.E. et al. Synthesis and surface expression of hyaluronan by dendritic cells and its potential role in antigen presentation. J. Immunol. 169, 4322–4331 (2002).

    Article  CAS  Google Scholar 

  29. Wang, H., Zhan, Y., Xu, L., Feuerstein, G.Z. & Wang, X. Use of suppression subtractive hybridization for differential gene expression in stroke: discovery of CD44 gene expression and localization in permanent focal stroke in rats. Stroke 32, 1020–1027 (2001).

    Article  CAS  Google Scholar 

  30. Wang, M.J. et al. c-Jun N-terminal kinase and, to a lesser extent, p38 mitogen-activated protein kinase regulate inducible nitric oxide synthase expression in hyaluronan fragments-stimulated BV-2 microglia. J. Neuroimmunol. 146, 50–62 (2004).

    Article  CAS  Google Scholar 

  31. Perosa, S.R. et al. Extracellular matrix components are altered in the hippocampus, cortex, and cerebrospinal fluid of patients with mesial temporal lobe epilepsy. Epilepsia 43 Suppl. 5, 159–161 (2002).

    Article  CAS  Google Scholar 

  32. Margolis, R.U., Margolis, R.K., Chang, L.B. & Preti, C. Glycosaminoglycans of brain during development. Biochemistry 14, 85–88 (1975).

    Article  CAS  Google Scholar 

  33. Jenkins, H.G. & Bachelard, H.S. Glycosaminoglycans in cortical autopsy samples from Alzheimer brain. J. Neurochem. 51, 1641–1645 (1988).

    Article  CAS  Google Scholar 

  34. Jenkins, H.G. & Bachelard, H.S. Developmental and age-related changes in rat brain glycosaminoglycans. J. Neurochem. 51, 1634–1640 (1988).

    Article  CAS  Google Scholar 

  35. Liu, Y. et al. CD44 expression identifies astrocyte-restricted precursor cells. Dev. Biol. 276, 31–46 (2004).

    Article  CAS  Google Scholar 

  36. Nait-Oumesmar, B. et al. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur. J. Neurosci. 11, 4357–4366 (1999).

    Article  CAS  Google Scholar 

  37. Blakemore, W.F., Gilson, J.M. & Crang, A.J. The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors. Exp. Neurol. 184, 955–963 (2003).

    Article  Google Scholar 

  38. Lynn, B.D., Li, X., Cattini, P.A., Turley, E.A. & Nagy, J.I. Identification of sequence, protein isoforms, and distribution of the hyaluronan-binding protein RHAMM in adult and developing rat brain. J. Comp. Neurol. 439, 315–330 (2001).

    Article  CAS  Google Scholar 

  39. Termeer, C. et al. Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).

    Article  CAS  Google Scholar 

  40. Chari, D.M. & Blakemore, W.F. New insights into remyelination failure in multiple sclerosis: implications for glial cell transplantation. Mult. Scler. 8, 271–277 (2002).

    Article  CAS  Google Scholar 

  41. Franklin, R.J. Why does remyelination fail in multiple sclerosis? Nat. Rev. Neurosci. 3, 705–714 (2002).

    Article  CAS  Google Scholar 

  42. Merrill, J.E. et al. Proliferation of astroglia and oligodendroglia in response to human T cell-derived factors. Science 224, 1428–1430 (1984).

    Article  CAS  Google Scholar 

  43. Zhang, S.C., Lundberg, C., Lipsitz, D., O'Connor, L.T. & Duncan, I.D. Generation of oligodendroglial progenitors from neural stem cells. J. Neurocytol. 27, 475–489 (1998).

    Article  CAS  Google Scholar 

  44. Bebo, B.F., Jr. et al. Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J. Immunol. 166, 2080–2089 (2001).

    Article  CAS  Google Scholar 

  45. Craig, A. et al. Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human. Exp. Neurol. 181, 231–240 (2003).

    Article  Google Scholar 

  46. Sherman, L. et al. Schwann cell tumors express characteristic patterns of CD44 splice variants. J. Neurooncol. 26, 171–184 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Marmer, N. Kleene, R. Fitzgerald, S. Foster, F. Chan, R. Xing and S. Weyte for technical assistance, and S. Kinney and A. Wagner for help with size-exclusion chromotography. This work was supported by grants from the US National Institutes of Health to L.S.S. (NS39550) and B.F.B. (AT001517), the National Multiple Sclerosis Society to L.S.S. (PP0975 and RG3512) and B.F.B. (RG3435), a March of Dimes Birth Defects Foundation grant to S.A.B. (6FY01-65) and a US National Institutes of Health core grant (RR00163) supporting the Oregon National Primate Research Center.

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Author notes

  1. Stephen A Back and Therese M F Tuohy: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pediatrics and Neurology, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, 97239, Oregon, USA

    Stephen A Back, Hanqin Chen, Andrew Craig & Ning Ling Luo

  2. Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, 97006, Oregon, USA

    Therese M F Tuohy, Nicholas Wallingford, Jaime Struve, Fatima Banine & Larry S Sherman

  3. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, Baltimore, 21224, Maryland, USA

    Ying Liu & Mahendra S Rao

  4. Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Ansi Chang & Bruce D Trapp

  5. Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, 97006, Oregon, USA

    Bruce F Bebo, Jr.

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Correspondence to Larry S Sherman.

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Supplementary information

Supplementary Fig. 1

CD44 expression becomes chronically elevated in demyelinated white matter. (PDF 75 kb)

Supplementary Fig. 2

CD44 is expressed by different cell types at different stages during EAE progression. (PDF 69 kb)

Supplementary Fig. 3

Hyaluronan is synthesized by reactive T cells and astrocytes and accumulates around oligodendrocytes expressing elevated CD44. (PDF 98 kb)

Supplementary Fig. 4

Timing of remyelination in the corpus callosum following lysolethicin injections. (PDF 119 kb)

Supplementary Fig. 5

Accumulation of OPCs in dysmyelinated white matter from Cnp1-Cd44 mice. (PDF 67 kb)

Supplementary Table 1 (PDF 19 kb)

Supplementary Methods (PDF 18 kb)

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Back, S., Tuohy, T., Chen, H. et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 11, 966–972 (2005). https://doi.org/10.1038/nm1279

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