Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation.
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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Stephen A
SA
Department of Pediatrics, School of Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Tuohy
Therese M F
TM
Chen
Hanqin
H
Wallingford
Nicholas
N
Craig
Andrew
A
Struve
Jaime
J
Luo
Ning Ling
NL
Banine
Fatima
F
Liu
Ying
Y
Chang
Ansi
A
Trapp
Bruce D
BD
Bebo
Bruce F
BF
Rao
Mahendra S
MS
Sherman
Larry S
LS
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D003711:Demyelinating Diseases / Q000503:physiopathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000503:physiopathology; D009836:Oligodendroglia / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology
D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid