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      Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases : Roadmap to the Clinic

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          Abstract

          Exosomes are small membrane-bound vesicles of endocytic origin that are actively secreted. The potential of exosomes as effective communicators of biological signaling in myocardial function has previously been investigated, and a recent explosion in exosome research not only underscores their significance in cardiac physiology and pathology, but also draws attention to methodological limitations of studying these extracellular vesicles. In this review, we discuss recent advances and challenges in exosome research with an emphasis on scientific innovations in isolation, identification, and characterization methodologies, and we provide a comprehensive summary of web-based resources available in the field. Importantly, we focus on the biology and function of exosomes, highlighting their fundamental role in cardiovascular pathophysiology to further support potential applications of exosomes as biomarkers and therapeutics for cardiovascular diseases.

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          Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

          Clotilde Théry, Kenneth W Witwer, Elena Aikawa … (2019)
          ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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            Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.

            Hadi Valadi, Karin Ekström, Apostolos Bossios … (2007)
            Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).
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              Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles.

              Marina Colombo, Graça Raposo, Clotilde Théry (2014)
              In the 1980s, exosomes were described as vesicles of endosomal origin secreted from reticulocytes. Interest increased around these extracellular vesicles, as they appeared to participate in several cellular processes. Exosomes bear proteins, lipids, and RNAs, mediating intercellular communication between different cell types in the body, and thus affecting normal and pathological conditions. Only recently, scientists acknowledged the difficulty of separating exosomes from other types of extracellular vesicles, which precludes a clear attribution of a particular function to the different types of secreted vesicles. To shed light into this complex but expanding field of science, this review focuses on the definition of exosomes and other secreted extracellular vesicles. Their biogenesis, their secretion, and their subsequent fate are discussed, as their functions rely on these important processes.
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                Author and article information

                Contributors
                Susmita Sahoo
                Marta Adamiak
                Prabhu Mathiyalagan
                Franziska Kenneweg
                Sabine Kafert-Kasting
                Thomas Thum
                Journal
                Journal ID (nlm-ta): Circulation
                Journal ID (iso-abbrev): Circulation
                Journal ID (publisher-id): CIR
                Title: Circulation
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0009-7322
                ISSN (Electronic): 1524-4539
                Publication date (Electronic): 06 April 2021
                Publication date (Print): 06 April 2021
                Volume: 143
                Issue: 14
                Pages: 1426-1449
                Affiliations
                [1 ]Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York (S.S., M.A., P.M.).
                [2 ]Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (F.K., S.K-K., T.T.), Hannover Medical School, Germany.
                [3 ]REBIRTH Center for Translational Regenerative Medicine (T.T.), Hannover Medical School, Germany.
                [4 ]Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (S.K-K., T.T.).
                Author notes
                Thomas Thum, MD, PhD, Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany; Email thum.thomas@ 123456mh-hannover.de
                Susmita Sahoo, PhD, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574. Email susmita.sahoo@ 123456mssm.edu
                Article
                Accession ID: 00009
                DOI: 10.1161/CIRCULATIONAHA.120.049254
                PMC ID: 8021236
                PubMed ID: 33819075
                SO-VID: 7b3a057b-6dc8-4870-bb1b-c0a6252b3708
                Copyright © © 2021 The Authors.
                License:

                Circulation 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 License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.

                History
                Categories
                Subject: 10015
                Subject: 10017
                Subject: 10018
                Subject: 10042
                Subject: State of the Art
                Subject: In Depth
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: biomarkers,cardiovascular diseases,extracellular vesicles,exosomes,therapeutics
                Data availability:
                Keywords: biomarkers, cardiovascular diseases, extracellular vesicles, exosomes, therapeutics

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