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      Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis

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          Abstract

          Fibrosis is a significant global health problem associated with many inflammatory and degenerative diseases affecting multiple organs, individually or simultaneously. Fibrosis develops when extracellular matrix (ECM) remodeling becomes excessive or uncontrolled and is associated with nearly all forms of heart disease. Cardiac fibroblasts and myofibroblasts are the main effectors of ECM deposition and scar formation. The heart is a complex multicellular organ, where the various resident cell types communicate between themselves and with cells of the blood and immune systems. Exosomes, which are small extracellular vesicles, (EVs), contribute to cell-to-cell communication and their pathophysiological relevance and therapeutic potential is emerging. Here, we will critically review the role of endogenous exosomes as possible fibrosis mediators and discuss the possibility of using stem cell-derived and/or engineered exosomes as anti-fibrotic agents.

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          Most cited references95

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          The transcriptional landscape of the mammalian genome.

          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            Regulated portals of entry into the cell.

            The plasma membrane is the interface between cells and their harsh environment. Uptake of nutrients and all communication among cells and between cells and their environment occurs through this interface. 'Endocytosis' encompasses several diverse mechanisms by which cells internalize macromolecules and particles into transport vesicles derived from the plasma membrane. It controls entry into the cell and has a crucial role in development, the immune response, neurotransmission, intercellular communication, signal transduction, and cellular and organismal homeostasis. As the complexity of molecular interactions governing endocytosis are revealed, it has become increasingly clear that it is tightly coordinated and coupled with overall cell physiology and thus, must be viewed in a broader context than simple vesicular trafficking.
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              Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.

              Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                02 March 2020
                March 2020
                : 9
                : 3
                : 592
                Affiliations
                [1 ]National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; roman.tikhomirov19@ 123456imperial.ac.uk (R.T.); b.reilly-odonnell@ 123456imperial.ac.uk (B.R.-O.); f.catapano@ 123456imperial.ac.uk (F.C.); j.gorelik@ 123456imperial.ac.uk (J.G.)
                [2 ]Department of Surgery, Dentistry, Pediatrics and Gynecology, Cardiovascular Science, The University of Verona, Policlinico G., B. Rossi, P.le. La Scuro 10, 37134 Verona, Italy; giuseppe.faggian@ 123456univr.it (G.F.); Fabio.martelli@ 123456grupposandonato.it (F.M.)
                [3 ]Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese Milano, Italy
                Author notes
                [* ]Correspondence: c.emanueli@ 123456imperial.ac.uk ; Tel.: +44-(0)2-75943409
                Author information
                https://orcid.org/0000-0003-0183-3701
                https://orcid.org/0000-0001-5371-5761
                https://orcid.org/0000-0002-6586-0170
                https://orcid.org/0000-0002-8624-7738
                Article
                cells-09-00592
                10.3390/cells9030592
                7140485
                32131460
                7161eb75-c51e-4c59-90a0-01c0297d8124
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 December 2019
                : 27 February 2020
                Categories
                Review

                cardiac fibrosis,heart failure,extracellular vesicle (evs),evs engineering,exosomes,micrornas,noncoding rnas,stem cells

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