Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis.
Mol Ther
; 29(4): 1439-1458, 2021 04 07.
Article
de En
| MEDLINE
| ID: mdl-33309882
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-iCreERT2CAG-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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Vieillissement de la cellule
/
Accident vasculaire cérébral
/
Récepteurs couplés aux protéines G
/
Gaine de myéline
Type d'étude:
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
Mol Ther
Sujet du journal:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Année:
2021
Type de document:
Article
Pays d'affiliation:
Italie