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.

Reviewing Editor

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

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).

Version 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.

Metrics

  • 3,059
    Page views
  • 350
    Downloads
  • 13
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.51735

Further reading

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

    1. Medicine
    2. Neuroscience
    Luisa Fassi, Shachar Hochman ... Roi Cohen Kadosh
    Research Article

    In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual’s subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants’ subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.