Contrastingmyelin damage through the generation ofnewmye- linating oligodendrocytes represents a promising approach to promote functional recoveryafter stroke.Here, we askedwhether activation of microglia and monocyte-derived macrophages af- fects the regenerative process sustained byG protein-coupled re- ceptor 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 af- ter injury, whereas they lose their pro-resolving capacity and ac- quire a dystrophic “senescent-like” phenotype at later stages. Intracerebral infusion of regenerative microglia-derived extra- cellular vesicles (EVs) restores protectivemicroglia/macrophages functions, limiting their senescence during the post-stroke phase, and enhances thematurationofGFP+OPCs at lesionborders, re- sulting in ameliorated neurological functionality. In vitro exper- iments showthatEV-carried transmembrane tumor necrosis fac- tor (tmTNF) mediates the pro-differentiating effects on OPCs, with future implications for regenerative therapies.

Microglial vesicles improve post-stroke recovery by preventing immune cell senescence and favoring oligodendrogenesis / S. Raffaele, P. Gelosa, E. Bonfanti, M. Lombardi, L. Castiglioni, M. Cimino, L. Sironi, M.P. Abbracchio, C. Verderio, M. Fumagalli. - In: MOLECULAR THERAPY. - ISSN 1525-0016. - 29:4(2021 Apr 07), pp. 1439-1458. [10.1016/j.ymthe.2020.12.009]

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

S. Raffaele
Primo
;
P. Gelosa
Secondo
;
E. Bonfanti;L. Castiglioni;L. Sironi;M.P. Abbracchio;M. Fumagalli
Ultimo
2021-04-07

Abstract

Contrastingmyelin damage through the generation ofnewmye- linating oligodendrocytes represents a promising approach to promote functional recoveryafter stroke.Here, we askedwhether activation of microglia and monocyte-derived macrophages af- fects the regenerative process sustained byG protein-coupled re- ceptor 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 af- ter injury, whereas they lose their pro-resolving capacity and ac- quire a dystrophic “senescent-like” phenotype at later stages. Intracerebral infusion of regenerative microglia-derived extra- cellular vesicles (EVs) restores protectivemicroglia/macrophages functions, limiting their senescence during the post-stroke phase, and enhances thematurationofGFP+OPCs at lesionborders, re- sulting in ameliorated neurological functionality. In vitro exper- iments showthatEV-carried transmembrane tumor necrosis fac- tor (tmTNF) mediates the pro-differentiating effects on OPCs, with future implications for regenerative therapies.
cerebral ischemia; extracellular vesicles; functional recovery; GPR17 receptor; microglia; neuroinflammation; oligodendrocyte precursor cells; remyelination; TNF; tumor necrosis factor
Settore BIO/14 - Farmacologia
10-dic-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/808898
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