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Updated: Jul 27, 2025
Characterization of Immune Cell-derived Extracellular Vesicles and Studying Functional Impact on Cell Environment
Published on: June 2, 2020
Mesenchymal-Derived Extracellular Vesicles Enhance Microglia-mediated Synapse Remodeling after Cortical Injury in
Yuxin Zhou1, Hrishti Bhatt1, Chromewell A Mojica1
1Boston University Chobanian & Avedisian School of Medicine.
Abstract:
Understanding the microglial neuro-immune interactions in the primate brain is vital to developing therapeutics for cortical injury, such as stroke. Our previous work showed that mesenchymal-derived extracellular vesicles (MSC-EVs) enhanced motor recovery in aged rhesus monkeys post-injury of primary motor cortex (M1), by promoting homeostatic ramified microglia, reducing injury-related neuronal hyperexcitability, and enhancing synaptic plasticity in perilesional cortices. The current study addresses how these injury- and recovery-associated changes relate to structural and molecular interactions between microglia and neuronal synapses. Using multi-labeling immunohistochemistry, high resolution microscopy, and gene expression analysis, we quantified co-expression of synaptic markers (VGLUTs, GLURs, VGAT, GABARs), microglia markers (Iba-1, P2RY12), and C1q, a complement pathway protein for microglia-mediated synapse phagocytosis, in perilesional M1 and premotor cortices (PMC) of monkeys with intravenous infusions of either vehicle (veh) or EVs post-injury. We compared this lesion cohort to aged-matched non-lesion controls. Our findings revealed a lesion-related loss of excitatory synapses in perilesional areas, which was ameliorated by EV treatment. Further, we found region-dependent effects of EV on microglia and C1q expression. In perilesional M1, EV treatment and enhanced functional recovery were associated with increased expression of C1q + hypertrophic microglia, which are thought to have a role in debris-clearance and anti-inflammatory functions. In PMC, EV treatment was associated with decreased C1q + synaptic tagging and microglial-spine contacts. Our results provided evidence that EV treatment facilitated synaptic plasticity by enhancing clearance of acute damage in perilesional M1, and thereby preventing chronic inflammation and excessive synaptic loss in PMC. These mechanisms may act to preserve synaptic cortical motor networks and a balanced normative M1/PMC synaptic connectivity to support functional recovery after injury.
Insights
Mesenchymal-derived extracellular vesicles (MSC-EVs) promote recovery after primate brain injury by enhancing microglial interactions and synaptic plasticity. EV treatment aids debris clearance and prevents chronic inflammation, preserving motor networks for functional recovery.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Microglial neuro-immune interactions are crucial for primate brain injury recovery, particularly after stroke.
- Mesenchymal-derived extracellular vesicles (MSC-EVs) previously enhanced motor recovery in aged rhesus monkeys post-M1 injury.
- Understanding microglia-synapse interactions is key to elucidating MSC-EVs' therapeutic mechanisms.
Approach:
- Investigated structural and molecular interactions between microglia and neuronal synapses post-cortical injury.
- Utilized multi-labeling immunohistochemistry, high-resolution microscopy, and gene expression analysis.
- Quantified synaptic markers, microglia markers (Iba-1, P2RY12), and C1q in perilesional M1 and premotor cortices (PMC) of vehicle- or EV-treated monkeys.
Key Points:
- EV treatment ameliorated lesion-related loss of excitatory synapses.
- EVs showed region-dependent effects on microglia and C1q expression.
- In M1, EVs increased C1q+ hypertrophic microglia, aiding debris clearance.
- In PMC, EVs decreased C1q+ synaptic tagging and microglial-spine contacts.
Conclusions:
- EV treatment facilitates synaptic plasticity by enhancing acute damage clearance in M1.
- EVs prevent chronic inflammation and excessive synaptic loss in PMC, preserving motor networks.
- MSC-EVs support functional recovery by maintaining balanced cortical synaptic connectivity.
