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      Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          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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          Most cited references38

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          Therapeutic applications of extracellular vesicles: clinical promise and open questions.

          This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury.
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            Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury.

            Multipotent human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after experimental traumatic brain injury (TBI). The present study was designed to investigate whether systemic administration of cell-free exosomes generated from hMSCs cultured in 2-dimensional (2D) conventional conditions or in 3-dimensional (3D) collagen scaffolds promote functional recovery and neurovascular remodeling in rats after TBI. Wistar rats were subjected to TBI induced by controlled cortical impact; 24 h later tail vein injection of exosomes derived from hMSCs cultured under 2D or 3D conditions or an equal number of liposomes as a treatment control were performed. The modified Morris water maze, neurological severity score and footfault tests were employed to evaluate cognitive and sensorimotor functional recovery. Animals were sacrificed at 35 days after TBI. Histological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Compared with liposome-treated control, exosome-treatments did not reduce lesion size but significantly improved spatial learning at 33-35 days measured by the Morris water maze test, and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatments significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn mature neurons in the dentate gyrus as well as reduced neuroinflammation. Exosomes derived from hMSCs cultured in 3D scaffolds provided better outcome in spatial learning than exosomes from hMSCs cultured in the 2D condition. In conclusion, hMSC-generated exosomes significantly improve functional recovery in rats after TBI, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing neuroinflammation. Thus, exosomes derived from hMSCs may be a novel cell-free therapy for TBI, and hMSC-scaffold generated exosomes may selectively enhance spatial learning.
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              The use of pigs in neuroscience: modeling brain disorders.

              The use of pigs in neuroscience research has increased in the past decade, which has seen broader recognition of the potential of pigs as an animal for experimental modeling of human brain disorders. The volume of available background data concerning pig brain anatomy and neurochemistry has increased considerably in recent years. The pig brain, which is gyrencephalic, resembles the human brain more in anatomy, growth and development than do the brains of commonly used small laboratory animals. The size of the pig brain permits the identification of cortical and subcortical structures by imaging techniques. Furthermore, the pig is an increasingly popular laboratory animal for transgenic manipulations of neural genes. The present paper focuses on evaluating the potential for modeling symptoms, phenomena or constructs of human brain diseases in pigs, the neuropsychiatric disorders in particular. Important practical and ethical aspects of the use of pigs as an experimental animal as pertaining to relevant in vivo experimental brain techniques are reviewed. Finally, current knowledge of aspects of behavioral processes including learning and memory are reviewed so as to complete the summary of the status of pigs as a species suitable for experimental models of diverse human brain disorders.
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                Author and article information

                Journal
                Stroke
                Stroke
                STR
                Stroke
                Lippincott Williams & Wilkins
                0039-2499
                1524-4628
                May 2018
                12 April 2018
                : 49
                : 5
                : 1248-1256
                Affiliations
                [1 ] 1From the ArunA Biomedical, Athens, GA (R.L.W., S.L. Scoville, T.A.T., R.L.S)
                [2 ] 2Regenerative Bioscience Center (R.L.W., E.E.K., B.J.J., S.S., F.D.W., S.L. Stice)
                [3 ] 3Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences (E.E.K., F.D.W.)
                [4 ] 4University of Georgia, Rhodes Center for Animal and Dairy Science, Athens; and Department of Neurology, Augusta University, GA (D.C.H.).
                Author notes
                Correspondence to Steven L. Stice, PhD, ArunA Biomedical, Athens, GA 30602. E-mail sstice@ 123456arunabiomedical.com
                Article
                00032
                10.1161/STROKEAHA.117.020353
                5916046
                29650593
                f0e18ff2-0c54-46e3-a07b-4a1100f043d5
                © 2018 The Authors.

                Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                History
                : 5 December 2017
                : 28 February 2018
                : 12 March 2018
                Categories
                10012
                10014
                10053
                10155
                10178
                Original Contributions
                Basic Sciences
                Custom metadata
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                brain ischemia,extracellular vesicles,magnetic resonance imaging,stroke,white matter

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