Abstract
Myelin destruction is followed by resident glia activation and mobilization of endogenous progenitors (OPC) which participate in myelin repair. Here we show that in response to demyelination, mature oligodendrocytes (OLG) bordering the lesion express Ndst1, a key enzyme for heparan sulfates (HS) synthesis. Ndst1+ OLG form a belt that demarcates lesioned from intact white matter. Mice with selective inactivation of Ndst1 in the OLG lineage display increased lesion size, sustained microglia and OPC reactivity. HS production around the lesion allows Sonic hedgehog (Shh) binding and favors the local enrichment of this morphogen involved in myelin regeneration. In MS patients, Ndst1 is also found overexpressed in oligodendroglia and the number of Ndst1-expressing oligodendroglia is inversely correlated with lesion size and positively correlated with remyelination potential. Our study suggests that mature OLG surrounding demyelinated lesions are not passive witnesses but contribute to protection and regeneration by producing HS.
Highlights
IntroductionMyelin loss remains in defined areas, rather than expanding to involve all of the white matter, and the mechanism by which demyelinated lesions stop expanding is not understood
In multiple sclerosis (MS), OLG are the target of inflammatory and immune attacks and their death results in multiple focal demyelinated lesions in the CNS
One of the most robustly and significantly up-regulated genes after demyelination was Ndst1, a key enzyme of heparan sulfates (HS) proteoglycan synthesis
Summary
Myelin loss remains in defined areas, rather than expanding to involve all of the white matter, and the mechanism by which demyelinated lesions stop expanding is not understood. Remyelination involves OPC recruitment to the lesion, differentiation into myelin forming cells and remyelination of denuded axons, and the success of this depends on environmental context, including secreted factors from neighboring cells [1, 2]. This repair process, which occurs spontaneously in MS patients, is highly variable between patients and between lesions [2]. Regenerative failure is mainly attributed to defects in OPC recruitment towards the demyelinated areas [3] and/or to their incapacity to differentiate into myelinating OLG at the lesion site [1, 4,5,6]
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