Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production

  1. Magali Macchi
  2. Karine Magalon
  3. Céline Zimmer
  4. Elitsa Peeva
  5. Bilal El Waly
  6. Béatrice Brousse
  7. Sarah Jaekel
  8. Kay Grobe
  9. Friedemann Kiefer
  10. Anna Williams
  11. Myriam Cayre
  12. Pascale Durbec  Is a corresponding author
  1. Aix Marseille University CNRS, France
  2. University of Edinburgh, United Kingdom
  3. University of Muenster, Germany
  4. 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.

Article and author information

Author details

  1. Magali Macchi

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Karine Magalon

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Céline Zimmer

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Elitsa Peeva

    Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Bilal El Waly

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2991-3754
  6. Béatrice Brousse

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah Jaekel

    Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Kay Grobe

    Physiological Chemistry, University of Muenster, Muenster, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8385-5877
  9. Friedemann Kiefer

    Max Planck Institute for Molecular Biomedicine, Max Planck Institute, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Anna Williams

    Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Myriam Cayre

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Pascale Durbec

    IBDM UMR7288, Aix Marseille University CNRS, Marseille, France
    For correspondence
    pascale.durbec@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9660-1809

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

  1. Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Germany

Publication history

  1. Received: September 17, 2019
  2. Accepted: June 9, 2020
  3. Accepted Manuscript published: June 9, 2020 (version 1)
  4. 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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  1. Magali Macchi
  2. Karine Magalon
  3. Céline Zimmer
  4. Elitsa Peeva
  5. Bilal El Waly
  6. Béatrice Brousse
  7. Sarah Jaekel
  8. Kay Grobe
  9. Friedemann Kiefer
  10. Anna Williams
  11. Myriam Cayre
  12. Pascale Durbec
(2020)
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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