Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis

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 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 (GFP+) OPCs after permanent middle cerebral artery occlusion. By microglia/macrophages pharmacological depletion studies, we show that innate immune cells favour GFP+ OPCs reaction and limit myelin damage early after injury, while 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 TNFα mediates the pro-differentiating effects on OPCs, with future implications for regenerative therapies.