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      Signaling Pathways in Exosomes Biogenesis, Secretion and Fate

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          Abstract

          Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.

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          Most cited references68

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          Exosome secretion: molecular mechanisms and roles in immune responses.

          Exosomes are small membrane vesicles, secreted by most cell types from multivesicular endosomes, and thought to play important roles in intercellular communications. Initially described in 1983, as specifically secreted by reticulocytes, exosomes became of interest for immunologists in 1996, when they were proposed to play a role in antigen presentation. More recently, the finding that exosomes carry genetic materials, mRNA and miRNA, has been a major breakthrough in the field, unveiling their capacity to vehicle genetic messages. It is now clear that not only immune cells but probably all cell types are able to secrete exosomes: their range of possible functions expands well beyond immunology to neurobiology, stem cell and tumor biology, and their use in clinical applications as biomarkers or as therapeutic tools is an extensive area of research. Despite intensive efforts to understand their functions, two issues remain to be solved in the future: (i) what are the physiological function(s) of exosomes in vivo and (ii) what are the relative contributions of exosomes and of other secreted membrane vesicles in these proposed functions? Here, we will focus on the current ideas on exosomes and immune responses, but also on their mechanisms of secretion and the use of this knowledge to elucidate the latter issue. © 2011 John Wiley & Sons A/S.
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            Cellular internalization of exosomes occurs through phagocytosis.

            Exosomes play important roles in many physiological and pathological processes. However, the exosome-cell interaction mode and the intracellular trafficking pathway of exosomes in their recipient cells remain unclear. Here, we report that exosomes derived from K562 or MT4 cells are internalized more efficiently by phagocytes than by non-phagocytic cells. Most exosomes were observed attached to the plasma membrane of non-phagocytic cells, while in phagocytic cells these exosomes were found to enter via phagocytosis. Specifically, they moved to phagosomes together with phagocytic polystyrene carboxylate-modified latex beads (biospheres) and were further sorted into phagolysosomes. Moreover, exosome internalization was dependent on the actin cytoskeleton and phosphatidylinositol 3-kinase, and could be inhibited by the knockdown of dynamin2 or overexpression of a dominant-negative form of dynamin2. Further, antibody pretreatment assays demonstrated that tim4 but not tim1 was involved in exosomes uptake. We also found that exosomes did not enter the internalization pathway involving caveolae, macropinocytosis and clathrin-coated vesicles. Our observation that the cellular uptake of exosomes occurs through phagocytosis has important implications for exosome-cell interactions and the exosome intracellular trafficking pathway.
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              Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

              Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                28 March 2013
                June 2013
                : 4
                : 2
                : 152-170
                Affiliations
                [1 ]Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06123 Perugia, Italy; E-Mails: urbanel@ 123456unipg.it (L.U.); alessandro.magini@ 123456libero.it (A.M); alessandro.brozzi@ 123456gmail.com (A.B.); krma@ 123456iol.it (K.S.); alicepolchi@ 123456virgilio.it (A.P.); brunellatancini@ 123456virgilio.it (B.T.)
                [2 ]Department of Internal Medicine, Section of Biochemistry, University of Perugia, Via del Giochetto, 06123 Perugia, Italy; E-Mail: sandra.buratta@ 123456unipg.it
                [3 ]Centro di Eccellenza sui Materiali Innovatovi Nanostrutturati (CEMIN), University of Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: emiliani@ 123456unipg.it ; Tel.: +39-075-585-7436; Fax: +39-075-585-7436.
                Article
                genes-04-00152
                10.3390/genes4020152
                3899971
                24705158
                0c9c3813-23fe-4995-bd0c-7063ac6cc5de
                © 2013 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 license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 04 February 2013
                : 22 March 2013
                : 25 March 2013
                Categories
                Review

                : exosome,extracellular vesicles,microvesicles,endosome,lysosome,multivesicular bodies,signaling,cell-to-cell communication,wnt signaling,biomarkers

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