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      Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Stroke: Challenges and Progress

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          Abstract

          Stroke is the leading cause of physical disability among adults. Stem cells such as mesenchymal stem cells (MSCs) secrete a variety of bioactive substances, including trophic factors and extracellular vesicles (EVs), into the injured brain, which may be associated with enhanced neurogenesis, angiogenesis, and neuroprotection. EVs are circular membrane fragments (30 nm−1 μm) that are shed from the cell surface and harbor proteins, microRNAs, etc. Since 2013 when it was first reported that intravenous application of MSC-derived EVs in a stroke rat model improved neurological outcomes and increased angiogenesis and neurogenesis, many preclinical studies have shown that stem cell-derived EVs can be used in stroke therapy, as an alternative approach to stem cell infusion. Although scientific research regarding MSC-derived EV therapeutics is still at an early stage, research is rapidly increasing and is demonstrating a promising approach for patients with severe stroke. MSC therapies have already been tested in preclinical studies and clinical trials, and EV-mediated therapy has unique advantages over cell therapies in stroke patients, in terms of biodistribution (overcoming the first pass effect and crossing the blood-brain-barrier), cell-free paradigm (avoidance of cell-related problems such as tumor formation and infarcts caused by vascular occlusion), whilst offering an off-the-shelf approach for acute ischemic stroke. Recently, advances have been made in the understanding of the function and biogenesis of EVs and EVs therapeutics for various diseases. This review presents the most recent advances in MSC-derived EV therapy for stroke, focusing on the application of this strategy for stroke patients.

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          Most cited references85

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          A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

          Background There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). Methods This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. Results Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. Conclusion Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors
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            A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

            We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients.
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              Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

              Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                12 March 2019
                2019
                : 10
                : 211
                Affiliations
                [1] 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, South Korea
                [2] 2Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center , Seoul, South Korea
                [3] 3Medical Research Institute, Sungkyunkwan University School of Medicine , Seoul, South Korea
                [4] 4Stem cell and Regenerative Medicine Institute, Samsung Biomedical Research Institute , Seoul, South Korea
                Author notes

                Edited by: Pedro M. Pimentel-Coelho, Federal University of Rio de Janeiro, Brazil

                Reviewed by: Claire Rome, Université Grenoble Alpes, France; Jialing Liu, University of California, San Francisco, United States

                *Correspondence: Oh Young Bang ohyoung.bang@ 123456samsung.com

                This article was submitted to Stroke, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2019.00211
                6422999
                30915025
                99db5fb9-1aa5-4f5d-ae07-3eb93658b5e2
                Copyright © 2019 Bang and Kim.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 December 2018
                : 18 February 2019
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 117, Pages: 11, Words: 8585
                Categories
                Neurology
                Review

                Neurology
                stroke,ischemic stroke,extracellular vesicles,stem cells,mesenchymal stem cells,microrna
                Neurology
                stroke, ischemic stroke, extracellular vesicles, stem cells, mesenchymal stem cells, microrna

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