Glia. 2026 Nov;74(11):e70235. doi: 10.1002/glia.70235.
ABSTRACT
Promoting white matter repair is crucial for functional recovery after ischemic stroke. Our previous study has identified an IFN-γ-responsive microglia phenotype in the brain after stroke. However, its role in white matter repair remains poorly understood. Herein, we find that extracellular vesicles derived from IFN-γ-responsive microglia (IFN-γ EVs) are internalized by oligodendrocyte precursor cells (OPCs), leading to impaired OPCs proliferation, survival, and differentiation and reduced white matter repair in a murine transient middle cerebral artery occlusion (tMCAO) model. Mechanistically, miR-9-5p enrichment in IFN-γ EVs suppresses NEDD4 expression, a key regulator of myelination, leading to reduced OPCs maturation and white matter repair. Genetic interventions including miR-9-5p knockdown in IFN-γ EVs or NEDD4 overexpression in OPCs restore remyelination and functional recovery. Our findings demonstrate that IFN-γ EVs act as negative regulators of OPCs differentiation and remyelination following ischemic stroke via miR-9-5p/NEDD4 pathway. Targeting this signaling axis may represent a novel therapeutic strategy to enhance remyelination and functional recovery after stroke.
PMID:42768493 | DOI:10.1002/glia.70235