IFN
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γ
‐Responsive Microglia‐Derived Extracellular Vesicles Impair White Matter Repair After Stroke Through a
Dongliang Qian, Tongtong Xu, Yiyan Guo, Shiyu Deng, Yanqin Geng, Hanlai Li, Lin Gan, Qianyuan Lian, Jingjing Xu, Huaitong Yao, Jing Ye, Enkhbat Myagmartsend, Guo‐Yuan Yang, Jixian Wang, Yaohui Tang, Qingzhu An 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.