Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation

被引:469
作者
Back, SA
Tuohy, TMF
Chen, HQ
Wallingford, N
Craig, A
Struve, J
Luo, NL
Banine, F
Liu, Y
Chang, A
Trapp, BD
Bebo, BF
Rao, MS
Sherman, LS
机构
[1] Oregon Hlth Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA
[2] Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97239 USA
[3] Oregon Hlth Sci Univ, Dept Neurol, Sch Med, Portland, OR 97239 USA
[4] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA
[5] Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA
[6] Oregon Hlth Sci Univ, Inst Neurol Sci, Beaverton, OR 97006 USA
关键词
D O I
10.1038/nm1279
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:966 / 972
页数:7
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