Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation

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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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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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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