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      Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

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          Abstract

          Exosomes are served as substitutes for stem cell therapy, playing important roles in mediating heart repair during myocardial infarction injury. Evidence have indicated that lipopolysaccharide (LPS) pre‐conditioning bone marrow‐derived mesenchymal stem cells (BMSCs) and their secreted exosomes promote macrophage polarization and tissue repair in several inflammation diseases; however, it has not been fully elucidated in myocardial infarction (MI). This study aimed to investigate whether LPS‐primed BMSC‐derived exosomes could mediate inflammation and myocardial injury via macrophage polarization after MI. Here, we found that exosomes derived from BMSCs, in both Exo and L‐Exo groups, increased M2 macrophage polarization and decreased M1 macrophage polarization under LPS stimulation, which strongly depressed LPS‐dependent NF‐κB signalling pathway and partly activated the AKT1/AKT2 signalling pathway. Compared with Exo, L‐Exo had superior therapeutic effects on polarizing M2 macrophage in vitro and attenuated the post‐infarction inflammation and cardiomyocyte apoptosis by mediating macrophage polarization in mice MI model. Consequently, we have confidence in the perspective that low concentration of LPS pre‐conditioning BMSC‐derived exosomes may develop into a promising cell‐free treatment strategy for clinical treatment of MI.

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          Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.

          Human ESC-derived mesenchymal stem cell (MSC)-conditioned medium (CM) was previously shown to mediate cardioprotection during myocardial ischemia/reperfusion injury through large complexes of 50-100 nm. Here we show that these MSCs secreted 50- to 100-nm particles. These particles could be visualized by electron microscopy and were shown to be phospholipid vesicles consisting of cholesterol, sphingomyelin, and phosphatidylcholine. They contained coimmunoprecipitating exosome-associated proteins, e.g., CD81, CD9, and Alix. These particles were purified as a homogeneous population of particles with a hydrodynamic radius of 55-65 nm by size-exclusion fractionation on a HPLC. Together these observations indicated that these particles are exosomes. These purified exosomes reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury. Therefore, MSC mediated its cardioprotective paracrine effect by secreting exosomes. This novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair. Copyright 2009 Elsevier B.V. All rights reserved.
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            Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

            Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.
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              The inflammatory response in myocardial injury, repair, and remodelling.

              Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.
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                Author and article information

                Contributors
                liuningning@gzhmu.edu.cn , liushiming@gzhmu.edu.cn
                liuningning@gzhmu.edu.cn , liushiming@gzhmu.edu.cn
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                26 September 2019
                November 2019
                : 23
                : 11 ( doiID: 10.1111/jcmm.v23.11 )
                : 7617-7631
                Affiliations
                [ 1 ] Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
                Author notes
                [* ] Correspondence

                Ningning Liu and Shiming Liu, Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou, Guangdong 510260, China.

                Emails: liuningning@ 123456gzhmu.edu.cn (N.L.); liushiming@ 123456gzhmu.edu.cn (S.L.)

                Article
                JCMM14635
                10.1111/jcmm.14635
                6815833
                31557396
                © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Counts
                Figures: 7, Tables: 0, Pages: 15, Words: 7822
                Product
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81873474
                Award ID: 81570259
                Funded by: the Foundation of Guangzhou Medical University for Doctor Scientists
                Award ID: 2016C17
                Funded by: General Project from Guangzhou Education Commission
                Award ID: 1201610098
                Funded by: Guangzhou health and family planning science and technology project
                Award ID: 20181A011066
                Award ID: 20162A011018
                Funded by: Natural Science Foundation of Guangdong Province
                Award ID: 2017A030313796
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm14635
                November 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:28.10.2019

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