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Updated: Jun 6, 2026
Isolation and Flow Cytometric Assessment of Neuroimmune Interactions in a Mini-Stroke Murine Model
Published on: June 20, 2025
M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate
Yuanjia Zhang1, Jie Wu2,3, Leyi Liu2,3
1Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Abstract:
Ischemic stroke is a major cause of disability with few treatment options available. Microglia-driven neuroinflammation contributes significantly to stroke pathology, and promoting anti-inflammatory microglial phenotypes represents a promising strategy. Migrasomes are newly discovered organelles mediating intercellular communication, yet their role in ischemic stroke remains unexplored. This study demonstrates that M2 microglia-derived migrasome-enriched extracellular vesicles (EVs) exert potent neuroprotection in both OGD/R cell models and MCAO mice. These migrasome-enriched EVs were efficiently internalized by microglia, astrocytes, neurons, and microvascular endothelial cells, promoting microglial M2 polarization, suppressing astrocytic aberrant activation, reducing neuronal apoptosis, and enhancing angiogenesis. Intracerebral administration of M2 microglia-derived migrasome-enriched EVs significantly reduced infarct volume, ameliorated cerebral edema, improved cerebral blood flow, and accelerated neurological and cognitive recovery without detectable toxicity. Mechanistically, migrasome-enriched EVs activated the cAMP/EPAC1/Rap1 signaling pathway in microglia, leading to restored mitochondrial homeostasis. Collectively, these findings identify M2 microglia-derived migrasome-enriched EVs as novel intercellular messengers that orchestrate neurovascular unit recovery after ischemic stroke, positioning migrasome-enriched EVs as promising candidates for stroke therapy.
Insights
M2 microglia-derived migrasome-enriched extracellular vesicles (EVs) offer neuroprotection after ischemic stroke. These EVs reduce stroke damage and improve recovery by activating specific cell signaling pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Ischemic stroke is a leading cause of disability with limited treatments.
- Neuroinflammation driven by microglia exacerbates stroke pathology.
- Migrasomes, novel organelles, mediate cell communication but their stroke role is unknown.
Purpose of the Study:
- To investigate the therapeutic potential of M2 microglia-derived migrasome-enriched extracellular vesicles (EVs) in ischemic stroke.
- To elucidate the mechanisms underlying the neuroprotective effects of these EVs.
Main Methods:
- Utilized OGD/R cell models and MCAO mouse models of ischemic stroke.
- Administered M2 microglia-derived migrasome-enriched EVs.
- Assessed EV internalization, microglial polarization, astrocyte activation, neuronal apoptosis, angiogenesis, infarct volume, cerebral edema, blood flow, and neurological recovery.
- Investigated the cAMP/EPAC1/Rap1 signaling pathway and mitochondrial homeostasis.
Main Results:
- M2 microglia-derived migrasome-enriched EVs were internalized by various brain cells.
- EVs promoted M2 microglial polarization, reduced astrocyte and neuronal damage, and enhanced angiogenesis.
- EV treatment significantly decreased infarct volume, edema, and improved cerebral blood flow and neurological function.
- EVs activated the cAMP/EPAC1/Rap1 pathway, restoring mitochondrial homeostasis.
Conclusions:
- M2 microglia-derived migrasome-enriched EVs act as potent neuroprotective agents in ischemic stroke.
- These EVs orchestrate neurovascular unit recovery through intercellular communication.
- Migrasome-enriched EVs represent a promising therapeutic strategy for stroke treatment.
