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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.

Project description:ObjectiveTo determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm.MethodsIn a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.ResultsOf 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥0.07).ConclusionsWe found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS.Classification of evidenceThis study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.Clinical trial registrationClinicaltrials.gov identifier NCT01422616.

Project description:BackgroundFor acute ischaemic stroke patients, it is uncertain whether intravenous thrombolysis combined with statins might increase the therapeutic effect. Additionally, using high-intensity statins after thrombolysis may increase the risk of bleeding in patients. Asian stroke patients often take low-dose statins. It is speculated that reducing the dose of statins may improve the risk of bleeding.MethodsData from consecutive acute ischaemic stroke patients with intravenous thrombolysis were prospectively collected. Efficacy outcomes included NIHSS (National Institutes of Health Stroke Scale) score improvement at 7 days after admission and mRS (Modified Rankin Scale) improvement at 90 days. Safety outcomes included haemorrhage events (intracerebral haemorrhage and gastrointestinal haemorrhage) in the hospital and death events within 2 years.ResultsThe study finally included 215 patients. The statin group had a higher percentage of NIHSS improvement at 7 days (p < 0.001) and a higher percentage of a favourable functional outcome (FFO, mRS < = 2) (p < 0.001) at 90 days. The statin group had a lower percentage of intracerebral haemorrhage (p < 0.001) and gastrointestinal haemorrhage (p = 0.003) in the hospital and a lower percentage of death events (p < 0.001) within 2 years. Logistic regression indicated that statin use was significantly related to NIHSS improvement (OR = 4.697, p < 0.001), a lower percentage of intracerebral haemorrhage (OR = 0.372, p = 0.049) and gastrointestinal haemorrhage (OR = 0.023, p = 0.016), and a lower percentage of death events (OR = 0.072, p < 0.001).ConclusionFor acute ischaemic stroke patients after intravenous thrombolysis, the use of low-dose statins was related to NIHSS improvement at 7 days and inversely related to haemorrhage events in the hospital and death events within 2 years, especially for moderate stroke or noncardioembolic stroke patients.

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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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