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Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis
Stefano Raffaele1, Paolo Gelosa2, Elisabetta Bonfanti1
1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.
Abstract:
Contrasting myelin damage through the generation of new myelinating oligodendrocytes represents a promising approach to promote functional recovery after stroke. Here, we asked whether activation of microglia and monocyte-derived macrophages affects the regenerative process sustained by G protein-coupled receptor 17 (GPR17)-expressing oligodendrocyte precursor cells (OPCs), a subpopulation of OPCs specifically reacting to ischemic injury. GPR17-iCreERT2:CAG-eGFP reporter mice were employed to trace the fate of GPR17-expressing OPCs, labeled by the green fluorescent protein (GFP), after permanent middle cerebral artery occlusion. By microglia/macrophages pharmacological depletion studies, we show that innate immune cells favor GFP+ OPC reaction and limit myelin damage early after injury, whereas they lose their pro-resolving capacity and acquire a dystrophic "senescent-like" phenotype at later stages. Intracerebral infusion of regenerative microglia-derived extracellular vesicles (EVs) restores protective microglia/macrophages functions, limiting their senescence during the post-stroke phase, and enhances the maturation of GFP+ OPCs at lesion borders, resulting in ameliorated neurological functionality. In vitro experiments show that EV-carried transmembrane tumor necrosis factor (tmTNF) mediates the pro-differentiating effects on OPCs, with future implications for regenerative therapies.
Insights
Microglia and macrophages support myelin repair after stroke by promoting oligodendrocyte precursor cell (OPC) regeneration. Extracellular vesicles (EVs) from these immune cells restore function and enhance OPC maturation, offering a potential regenerative therapy.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Myelin repair via oligodendrocyte precursor cell (OPC) generation is key for stroke recovery.
- G protein-coupled receptor 17 (GPR17)-expressing OPCs are crucial in responding to ischemic injury.
- The role of microglia and macrophages in GPR17+ OPC regeneration post-stroke requires elucidation.
Purpose of the Study:
- To investigate the impact of microglia and monocyte-derived macrophages on GPR17+ OPCs after stroke.
- To determine if extracellular vesicles (EVs) can restore beneficial immune cell functions and promote repair.
- To explore the therapeutic potential of modulating immune responses for stroke recovery.
Main Methods:
- Utilized GPR17-iCreERT2:CAG-eGFP reporter mice to track GPR17+ OPCs post-stroke.
- Employed pharmacological depletion to study microglia/macrophage roles.
- Administered microglia-derived EVs to assess their therapeutic effects in vivo and in vitro.
Main Results:
- Innate immune cells initially support GPR17+ OPCs and limit early myelin damage.
- Immune cells later adopt a senescent phenotype, losing pro-resolving capacity.
- EV treatment restored immune cell function, reduced senescence, enhanced OPC maturation, and improved neurological function.
- EV-carried transmembrane TNF (tmTNF) was identified as a key mediator of OPC differentiation.
Conclusions:
- Microglia and macrophages play a dual role in stroke recovery, shifting from protective to detrimental.
- Microglia-derived EVs hold therapeutic potential by restoring immune cell function and promoting myelin regeneration.
- Targeting immune cell senescence and leveraging EVs may offer novel strategies for stroke rehabilitation.
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