Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

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, James A. Febery, Jeffrey A. Johnson, Jill H. Fowler, Tanja Kuhlmann, Anna Williams, Siddharthan Chandran, Martin Stangel, Andrew J. M. Howden, Giles E. Hardingham and Veronique E. Miron ()
Additional contact information
Irene Molina-Gonzalez: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Rebecca K. Holloway: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Zoeb Jiwaji: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Owen Dando: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Sarah A. Kent: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Katie Emelianova: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Amy F. Lloyd: University of Dundee
Lindsey H. Forbes: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Ayisha Mahmood: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
Thomas Skripuletz: Medizinische Hochschule Hannover
Viktoria Gudi: Medizinische Hochschule Hannover
James A. Febery: University of Edinburgh
Jeffrey A. Johnson: 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
Siddharthan Chandran: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School
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
Veronique E. Miron: United Kingdom Dementia Research Institute at The University of Edinburgh, Edinburgh Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39046-8

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