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Interferon-γ-Responsive Microglia-Derived Extracellular Vesicles Inhibited Neurogenesis After Stroke via

Tongtong Xu1,2, Dongliang Qian1, Shiyu Deng2

  • 1Department of Neurosurgery Huashan Hospital, Shanghai Medical College, Fudan University Shanghai China.

Journal of the American Heart Association
|February 20, 2026
PubMed
Abstract

Insights

Interferon-gamma EVs worsen stroke outcomes by inhibiting neural stem cell differentiation via the miR-199a-5p/SIRT1 pathway. Targeting this axis offers a new therapeutic strategy for ischemic stroke recovery.

Area of Science:

  • Neuroscience
  • Immunology
  • Stem Cell Biology

Background:

  • Microglia in the brain respond to interferon after central nervous system injury.
  • The precise roles and mechanisms of these microglia in neurological recovery are not fully understood.

Purpose of the Study:

  • To investigate the role of interferon-gamma-responsive microglia in neurological function recovery after ischemic stroke.
  • To elucidate the underlying molecular mechanisms, focusing on extracellular vesicles (EVs) and microRNAs (miRNAs).

Main Methods:

  • Used a mouse model of transient middle cerebral artery occlusion (stroke).
  • Employed single-cell RNA sequencing, immunostaining, qPCR, ELISA, and miRNA sequencing.
  • Isolated and administered interferon-gamma EVs to neural stem cells (NSCs) in vitro and in vivo, followed by neurobehavioral and histological assessments.

Main Results:

  • Interferon-gamma EVs were found in stroke brains and inhibited NSC survival and neuronal differentiation.
  • EV administration worsened brain injury, impaired neurobehavioral recovery, and reduced neurogenesis.
  • The miR-199a-5p/SIRT1 axis was identified as the key pathway mediating these inhibitory effects.

Conclusions:

  • Interferon-gamma EVs exacerbate ischemic stroke brain injury by inhibiting NSC survival and neuronal differentiation through the miR-199a-5p/SIRT1 pathway.
  • This pathway represents a novel therapeutic target for treating ischemic stroke.
Keywords:
extracellular vesiclesinterferon‐γ–responsive microglianeurogenesisstroke

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