Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 06 2023
08 06 2023
Historique:
received:
18
10
2022
accepted:
18
05
2023
medline:
12
6
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37291151
doi: 10.1038/s41467-023-39046-8
pii: 10.1038/s41467-023-39046-8
pmc: PMC10250470
doi:
Substances chimiques
NF-E2-Related Factor 2
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3372Subventions
Organisme : Medical Research Council
ID : MRC/V031260/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N02256/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M020827/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V031260/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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