Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation

Article metrics

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

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

  2. 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).

  3. 3

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

  4. 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).

  5. 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).

  6. 6

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

  7. 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).

  8. 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).

  9. 9

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

  10. 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).

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 15

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

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 26

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

  27. 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).

  28. 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).

  29. 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).

  30. 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).

  31. 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).

  32. 32

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

  33. 33

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

  34. 34

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

  35. 35

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

  36. 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).

  37. 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).

  38. 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).

  39. 39

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

  40. 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).

  41. 41

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

  42. 42

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

  43. 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).

  44. 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).

  45. 45

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

  46. 46

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

Download references

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.

Author information

Correspondence to Larry S Sherman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and Permissions

About this article

Further reading