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Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

Author

Listed:
  • Irene Molina-Gonzalez

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Rebecca K. Holloway

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Zoeb Jiwaji

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh)

  • Owen Dando

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh)

  • Sarah A. Kent

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    Wellcome Trust Translational Neuroscience PhD programme)

  • Katie Emelianova

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh)

  • Amy F. Lloyd

    (University of Dundee)

  • Lindsey H. Forbes

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Ayisha Mahmood

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Thomas Skripuletz

    (Medizinische Hochschule Hannover)

  • Viktoria Gudi

    (Medizinische Hochschule Hannover)

  • James A. Febery

    (University of Edinburgh)

  • Jeffrey A. Johnson

    (University of Wisconsin
    University of Wisconsin
    University of Wisconsin
    University of Wisconsin)

  • Jill H. Fowler

    (University of Edinburgh)

  • Tanja Kuhlmann

    (University Hospital Muenster)

  • Anna Williams

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh)

  • Siddharthan Chandran

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh)

  • Martin Stangel

    (Medizinische Hochschule Hannover)

  • Andrew J. M. Howden

    (University of Dundee)

  • Giles E. Hardingham

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh)

  • Veronique E. Miron

    (United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
    University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

Abstract

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

Suggested Citation

  • Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39046-8
    DOI: 10.1038/s41467-023-39046-8
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    References listed on IDEAS

    as
    1. Lucas Schirmer & Dmitry Velmeshev & Staffan Holmqvist & Max Kaufmann & Sebastian Werneburg & Diane Jung & Stephanie Vistnes & John H. Stockley & Adam Young & Maike Steindel & Brian Tung & Nitasha Goya, 2019. "Neuronal vulnerability and multilineage diversity in multiple sclerosis," Nature, Nature, vol. 573(7772), pages 75-82, September.
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