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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via
Yaying Song1, Rubing Shi2, Yingjun Liu3
1Department of Neurology, Renji Hospital of Shanghai Jiao Tong University, China (Y.S., L.H., Y.G.).
Background:
Small extracellular vesicles (sEVs) derived from M2 microglia (M2-microglia-derived small extracellular vesicles [M2-sEVs]) contribute to central nervous system repair, although the underlying mechanism remains unknown. In this study, we aimed to identify the mechanism through which microRNA-124 (miR-124) carried in sEVs promotes neural stem cell (NSC) proliferation and neuronal differentiation in the ischemic mouse brain.
Methods:
M2-sEVs with or without miR-124 knockdown were injected intravenously for 7 consecutive days after transient middle cerebral artery occlusion surgery. The atrophy volume, neurological score, and degree of neurogenesis were examined at different time points after ischemic attack. NSCs treated with different sEVs were subjected to proteomic analysis. Target protein concentrations were quantified, and subsequent bioinformatic analysis was conducted to explore the key signaling pathways.
Results:
M2-sEV transplantation promoted functional neurological recovery following transient middle cerebral artery occlusion injury. M2-sEV treatment decreased the brain atrophy volume, neurological score, and mortality rate. The effect was reserved by knockdown of miR-124 in M2-sEVs. M2-sEVs promoted proliferation and differentiation of mature neuronal NSCs in vivo. Proteomic analysis of NSC samples treated with M2-sEVs with and without miR-124 knockdown revealed that AAK1 (adaptor-associated protein kinase 1) was the key responding protein in NSCs. The binding of AAK1 to Notch promoted the differentiation of NSCs into neurons rather than astrocytes.
Conclusions:
Our data suggest that AAK1/Notch is the key pathway in NSCs that responds to the miR-124 carried within M2-sEVs in the ischemic brain. M2-sEVs carrying ample quantities of miR-124 promote functional recovery after ischemic stroke by enhancing NSC proliferation and differentiation. Targeting of M2-sEVs could represent a potential therapeutic strategy for brain recovery.
Insights
M2-microglia-derived small extracellular vesicles (M2-sEVs) carrying microRNA-124 (miR-124) enhance neural stem cell proliferation and neuronal differentiation. This promotes functional recovery after ischemic stroke by activating the AAK1/Notch pathway.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Molecular Biology
Background:
- Small extracellular vesicles (sEVs) from M2 microglia (M2-sEVs) show potential for central nervous system repair.
- The precise mechanism by which M2-sEVs promote repair, particularly their role in neural stem cell (NSC) behavior, is not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which microRNA-124 (miR-124) within M2-sEVs drives NSC proliferation and neuronal differentiation in the context of ischemic stroke.
- To identify key molecular pathways and proteins involved in M2-sEV-mediated neurogenesis and functional recovery.
Main Methods:
- In vivo administration of M2-sEVs (with and without miR-124 knockdown) to mice post-stroke (transient middle cerebral artery occlusion).
- Assessment of neurological function, brain atrophy, and neurogenesis.
- Proteomic analysis of NSCs treated with M2-sEVs to identify target proteins and signaling pathways, followed by bioinformatic analysis.
Main Results:
- M2-sEV transplantation significantly improved neurological function, reduced brain atrophy, and decreased mortality rates post-stroke.
- The beneficial effects of M2-sEVs were dependent on miR-124; knockdown reversed the improvements.
- M2-sEVs promoted NSC proliferation and differentiation into neurons, mediated by the AAK1/Notch signaling pathway, where AAK1 binding to Notch promotes neuronal differentiation.
Conclusions:
- The AAK1/Notch pathway in NSCs is a critical mediator of miR-124's effects from M2-sEVs in ischemic brain injury.
- M2-sEVs, rich in miR-124, offer a promising therapeutic strategy for ischemic stroke recovery by enhancing NSC-driven neurogenesis.
- Targeting M2-sEVs presents a potential avenue for developing novel treatments for brain repair.
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