Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production
- Aix Marseille University CNRS, France
- University of Edinburgh, United Kingdom
- University of Muenster, Germany
- Max Planck Institute, Germany
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Funding
Centre National de la Recherche Scientifique (financial support)
- Pascale Durbec
Aix-Marseille Université (Graduate student Fellowship and financial support)
- Pascale Durbec
Fondation pour la Recherche Médicale (DEQ20140329501)
- Pascale Durbec
Agence Nationale de la Recherche (France-bioimaging/PICSL infrastructure ANR-10-INSB-04-01)
- Pascale Durbec
Agence Nationale de la Recherche (ANR-15-CE16-0014-01)
- Pascale Durbec
AM*DEX NeuroMarseille Institute (AMX-19-IET-004)
- Pascale Durbec
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental and surgical protocols were performed following the guidelines established by the French Ministry of Agriculture (Animal Rights Division). The architecture and functioning rules of our animal house, as well as our experimental procedures have been approved by the 'Direction Départementale des Services Vétérinaires' and the ethic committee (ID numbers F1305521 and 2016071112151400 for animal house and research project,
Human subjects: Human postmortem unfixed frozen tissues were obtained from the UK Multiple Sclerosis Tissue Bank via a UK prospective donor scheme with full ethical approval (MREC/02/2/39).
Reviewing Editor
- Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Germany
Publication history
- Received: September 17, 2019
- Accepted: June 9, 2020
- Accepted Manuscript published: June 9, 2020 (version 1)
- Version of Record published: June 22, 2020 (version 2)
Copyright
© 2020, Macchi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production
eLife 9:e51735.
https://doi.org/10.7554/eLife.51735
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