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Low dose of extracellular vesicles identified that promote recovery after ischemic stroke.

ABSTRACT: BACKGROUND:Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100??g. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke. MATERIALS AND METHODS:For this purpose, various doses of EVs were tested in an in vitro oxygen-glucose deprivation (OGD) model of oligodendrocytes and neuronal ischemia. At least 50??g of EVs were necessary to induce proliferation and differentiation of oligodendrocyte and neurons in OGD conditions. For in vivo study, rats were subjected to subcortical stroke and various doses (50??g, 100??g, or 200??g) of EVs were intravenously administered after 24?h. RESULTS:All the animals in the EV groups showed significant improvement in functional tests, with an increase in tract connectivity and brain repair-associated markers, and a decrease in cell death and in astrocyte-marker expression. Cell proliferation was increased in the groups receiving 50??g and 100??g doses. Only the 50-?g dose was associated with significant increases in brain-derived neurotrophic factor expression. CONCLUSION:In conclusion, 50??g of EVs appears to be the minimal effective dose to enhance protection, brain repair, and recovery in subcortical ischemic stroke.

SUBMITTER: Otero-Ortega L

PROVIDER: S-EPMC7029550 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Low dose of extracellular vesicles identified that promote recovery after ischemic stroke.

Otero-Ortega Laura L Laso-García Fernando F Frutos Mari Carmen Gómez-de MCG Diekhorst Luke L Martínez-Arroyo Arturo A Alonso-López Elisa E García-Bermejo María Laura ML Rodríguez-Serrano Macarena M Arrúe-Gonzalo Mercedes M Díez-Tejedor Exuperio E Fuentes Blanca B Gutiérrez-Fernández María M

Stem cell research & therapy 20200219 1

<h4>Background</h4>Mesenchymal stem cell-derived extracellular vesicles (EVs) are one of the most promising therapeutics in protective and/or regenerative therapy in animal models of stroke using a dose of 100 μg. However, whether EVs dose is related to outcomes is not known. This study aimed to identify the optimal effective dose of EVs from adipose tissue-derived mesenchymal stem cells that promote functional recovery in subcortical stroke.<h4>Materials and methods</h4>For this purpose, variou ...[more]

PMID: 32075692

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Project description:BACKGROUND AND PURPOSE:Recent work from our group suggests that human neural stem cell-derived extracellular vesicle (NSC EV) treatment improves both tissue and sensorimotor function in a preclinical thromboembolic mouse model of stroke. In this study, NSC EVs were evaluated in a pig ischemic stroke model, where clinically relevant end points were used to assess recovery in a more translational large animal model. METHODS:Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO), and either NSC EV or PBS treatment was administered intravenously at 2, 14, and 24 hours post-MCAO. NSC EV effects on tissue level recovery were evaluated via magnetic resonance imaging at 1 and 84 days post-MCAO. Effects on functional recovery were also assessed through longitudinal behavior and gait analysis testing. RESULTS:NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs (0 of 7) versus control pigs (7 of 8). NSC EV-treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs 1-day post-MCAO. NSC EVs significantly reduced edema in treated pigs relative to control pigs, as assessed by improved diffusivity through apparent diffusion coefficient maps. NSC EVs preserved white matter integrity with increased corpus callosum fractional anisotropy values 84 days post-MCAO. Behavior and mobility improvements paralleled structural changes as NSC EV-treated pigs exhibited improved outcomes, including increased exploratory behavior and faster restoration of spatiotemporal gait parameters. CONCLUSIONS:This study demonstrated for the first time that in a large animal model novel NSC EVs significantly improved neural tissue preservation and functional levels post-MCAO, suggesting NSC EVs may be a paradigm changing stroke therapeutic.

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Low dose of extracellular vesicles identified that promote recovery after ischemic stroke.

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Low dose of extracellular vesicles identified that promote recovery after ischemic stroke.

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