Shedding light on the cell biology of extracellular vesicles (original) (raw)

• Schorey, J. S., Cheng, Y., Singh, P. P. & Smith, V. L. Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep. 16, 24–43 (2015).
  CAS PubMed Google Scholar
• Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).
  CAS PubMed PubMed Central Google Scholar
• Robinson, D. G., Ding, Y. & Jiang, L. Unconventional protein secretion in plants: a critical assessment. Protoplasma 253, 31–43 (2016).
  CAS PubMed Google Scholar
• Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987). This is the first report of exosomes as intraluminal vesicles of multivesicular endosomes that are secreted upon fusion of these endosomes with the plasma membrane, coining the term 'exosomes'.
  CAS PubMed Google Scholar
• Colombo, M., Raposo, G. & Thery, C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014).
  CAS PubMed Google Scholar
• Lo Cicero, A., Stahl, P. D. & Raposo, G. Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr. Opin. Cell Biol. 35, 69–77 (2015).
  CAS PubMed Google Scholar
• Yanez-Mo, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).
  PubMed Google Scholar
• Harding, C., Heuser, J. & Stahl, P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 97, 329–339 (1983).
  CAS PubMed Google Scholar
• Thery, C., Amigorena, S., Raposo, G. & Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. http://dx.doi.org/10.1002/0471143030.cb0322s30 (2006). This is the first exhaustive and detailed protocol providing isolation and characterization procedures of exosomes present in cell culture supernatants and biological fluids.
• Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).
  CAS PubMed PubMed Central Google Scholar
• Wasmuth, E. V., Januszyk, K. & Lima, C. D. Structure of an Rrp6-RNA exosome complex bound to poly(A) RNA. Nature 511, 435–439 (2014).
  CAS PubMed PubMed Central Google Scholar
• Trams, E. G., Lauter, C. J., Salem, N. Jr & Heine, U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim. Biophys. Acta 645, 63–70 (1981).
  CAS PubMed Google Scholar
• Harding, C., Heuser, J. & Stahl, P. Endocytosis and intracellular processing of transferrin and colloidal-gold transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur. J. Cell Biol. 35, 256–263 (1984).
  CAS PubMed Google Scholar
• Pan, B. T., Teng, K., Wu, C., Adam, M. & Johnstone, R. M. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J. Cell Biol. 101, 942–948 (1985).
  CAS PubMed Google Scholar
• Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996). Exploiting electron microscopy, biochemistry and functional assays, this manuscript shows for the first time that antigen-presenting cells secrete exosomes able to stimulate T cell proliferation.
  CAS PubMed Google Scholar
• Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med. 4, 594–600 (1998). This study using tumour-bearing mice reports that exosomes secreted by dendritic cells induce antitumoural immune responses in vivo.
  CAS PubMed Google Scholar
• Wolf, P. The nature and significance of platelet products in human plasma. Br. J. Haematol. 13, 269–288 (1967).
  CAS PubMed Google Scholar
• Stein, J. M. & Luzio, J. P. Ectocytosis caused by sublytic autologous complement attack on human neutrophils. The sorting of endogenous plasma-membrane proteins and lipids into shed vesicles. Biochem. J. 274, 381–386 (1991).
  CAS PubMed PubMed Central Google Scholar
• Sims, P. J., Faioni, E. M., Wiedmer, T. & Shattil, S. J. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J. Biol. Chem. 263, 18205–18212 (1988).
  CAS PubMed Google Scholar
• Satta, N. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J. Immunol. 153, 3245–3255 (1994).
  CAS PubMed Google Scholar
• Al-Nedawi, K. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10, 619–624 (2008).
  CAS PubMed Google Scholar
• Tricario, C., Clancy, J. & De Souza-Schorey, C. Biology and biogenesis of shed microvesicles. Small GTPases 1–13 (2016).
• Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).
  CAS PubMed PubMed Central Google Scholar
• Ma, L. et al. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res. 25, 24–38 (2015).
  CAS PubMed Google Scholar
• Nabhan, J. F., Hu, R., Oh, R. S., Cohen, S. N. & Lu, Q. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc. Natl Acad. Sci. USA 109, 4146–4151 (2012).
  CAS PubMed PubMed Central Google Scholar
• Gould, S. J. & Raposo, G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles 2, 20398 (2013).
  Google Scholar
• Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113, E968–E977 (2016).
  CAS PubMed PubMed Central Google Scholar
• Booth, A. M. et al. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell Biol. 172, 923–935 (2006).
  CAS PubMed PubMed Central Google Scholar
• Gerber, P. P. et al. Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate. J. Cell Biol. 209, 435–452 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kalra, H., Drummen, G. P. & Mathivanan, S. Focus on extracellular vesicles: introducing the next small big thing. Int. J. Mol. Sci. 17, 170 (2016).
  PubMed PubMed Central Google Scholar
• Minciacchi, V. R., Freeman, M. R. & Di Vizio, D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin. Cell Dev. Biol. 40, 41–51 (2015).
  CAS PubMed PubMed Central Google Scholar
• Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19–30 (2010). This study uses a medium-throughput RNA-interference screen for RAB GTPases to reveal the involvement of RAB27 in exosome secretion, providing further evidence that exosomes derive from secretory multivesicular endosomes.
  CAS PubMed Google Scholar
• Berson, J. F., Harper, D., Tenza, D., Raposo, G. & Marks, M. S. Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol. Biol. Cell 12, 3451–3464 (2001).
  CAS PubMed PubMed Central Google Scholar
• Klumperman, J. & Raposo, G. The complex ultrastructure of the endolysosomal system. Cold Spring Harbor Perspect. Biol. 6, a016857 (2014).
  Google Scholar
• Vidal, M., Mangeat, P. & Hoekstra, D. Aggregation reroutes molecules from a recycling to a shedding pathway during reticulocyte maturation. J. Cell Sci. 110, 1867–1877 (1997).
  CAS PubMed Google Scholar
• Zimmermann, P. et al. Syndecan recycling [corrected] is controlled by syntenin-PIP2 interaction and Arf6. Dev. Cell 9, 377–388 (2005).
  CAS PubMed Google Scholar
• Baietti, M. F. et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 14, 677–685 (2012). This study reveals the involvement of a particular machinery required for exosome biogenesis and signalling through the interaction of ESCRTs, ALIX and syndecans.
  CAS PubMed Google Scholar
• D'Souza-Schorey, C. & Chavrier, P. ARF proteins: roles in membrane traffic and beyond. Nat. Rev. Mol. Cell Biol. 7, 347–358 (2006).
  CAS PubMed Google Scholar
• Muralidharan-Chari, V. et al. ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875–1885 (2009). This is the first report showing a mechanism for microvesicle release through the involvement of ARF6 and cytoskeletal rearrangements. It also shows that microvesicles but not exosomes carry metalloproteases able to digest the extracellular matrix.
  CAS PubMed PubMed Central Google Scholar
• Wang, T. et al. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc. Natl Acad. Sci. USA 111, E3234–E3242 (2014).
  CAS PubMed PubMed Central Google Scholar
• Hurley, J. H. ESCRT complexes and the biogenesis of multivesicular bodies. Curr. Opin. Cell Biol. 20, 4–11 (2008).
  CAS PubMed PubMed Central Google Scholar
• Tamai, K. et al. Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem. Biophys. Res. Commun. 399, 384–390 (2010).
  CAS PubMed Google Scholar
• Colombo, M. et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553–5565 (2013). This study uses a high-throughput RNA-interference screen targeting ESCRT subunits and accessory proteins to reveal a role for selected ESCRT components in modulation of exosome secretion and composition.
  CAS PubMed Google Scholar
• Stuffers, S., Sem Wegner, C., Stenmark, H. & Brech, A. Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10, 925–937 (2009).
  CAS PubMed Google Scholar
• Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).
  CAS PubMed Google Scholar
• Goni, F. M. & Alonso, A. Effects of ceramide and other simple sphingolipids on membrane lateral structure. Biochim. Biophys. Acta 1788, 169–177 (2009).
  CAS PubMed Google Scholar
• Kajimoto, T., Okada, T., Miya, S., Zhang, L. & Nakamura, S. Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat. Commun. 4, 2712 (2013).
  PubMed Google Scholar
• Theos, A. C. et al. A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev. Cell 10, 343–354 (2006).
  CAS PubMed PubMed Central Google Scholar
• van Niel, G. et al. The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev. Cell 21, 708–721 (2011).
  CAS PubMed PubMed Central Google Scholar
• van Niel, G. et al. Apolipoprotein E regulates amyloid formation within endosomes of pigment cells. Cell Rep. 13, 43–51 (2015).
  CAS PubMed Google Scholar
• Gauthier, S. A. et al. Enhanced exosome secretion in Down syndrome brain - a protective mechanism to alleviate neuronal endosomal abnormalities. Acta Neuropathol. Commun. 5, 65 (2017).
  PubMed PubMed Central Google Scholar
• Buschow, S. I. et al. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10, 1528–1542 (2009). This study reports that upon interaction with T cells, dendritic cells target MHC II molecules towards exosome secretion by using a multivesicular body pathway distinct from those employed by dendritic cells to target MHC II molecules towards lysosomal degradation.
  CAS PubMed Google Scholar
• Chairoungdua, A., Smith, D. L., Pochard, P., Hull, M. & Caplan, M. J. Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J. Cell Biol. 190, 1079–1091 (2010).
  CAS PubMed PubMed Central Google Scholar
• Charrin, S., Jouannet, S., Boucheix, C. & Rubinstein, E. Tetraspanins at a glance. J. Cell Sci. 127, 3641–3648 (2014).
  CAS PubMed Google Scholar
• Zimmerman, B. et al. Crystal structure of a full-length human tetraspanin reveals a cholesterol-binding pocket. Cell 167, 1041–1051.e11 (2016).
  CAS PubMed PubMed Central Google Scholar
• Odintsova, E. et al. Metastasis suppressor tetraspanin CD82/KAI1 regulates ubiquitylation of epidermal growth factor receptor. J. Biol. Chem. 288, 26323–26334 (2013).
  CAS PubMed PubMed Central Google Scholar
• Thery, C. et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 166, 7309–7318 (2001).
  CAS PubMed Google Scholar
• Geminard, C., De Gassart, A., Blanc, L. & Vidal, M. Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TfR for sorting into exosomes. Traffic 5, 181–193 (2004).
  CAS PubMed Google Scholar
• de Gassart, A., Geminard, C., Fevrier, B., Raposo, G. & Vidal, M. Lipid raft-associated protein sorting in exosomes. Blood 102, 4336–4344 (2003).
  CAS PubMed Google Scholar
• Buschow, S. I., Liefhebber, J. M., Wubbolts, R. & Stoorvogel, W. Exosomes contain ubiquitinated proteins. Blood Cells Mol. Dis. 35, 398–403 (2005).
  CAS PubMed Google Scholar
• Luhtala, N., Aslanian, A., Yates, J. R. 3rd & Hunter, T. Secreted glioblastoma nanovesicles contain intracellular signaling proteins and active Ras incorporated in a farnesylation-dependent manner. J. Biol. Chem. 292, 611–628 (2017).
  CAS PubMed Google Scholar
• Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007). This article demonstrates that exosomes contain mRNAs and miRNAs and mediate their transfer between cells.
  CAS PubMed Google Scholar
• Nolte-'t Hoen, E. N. et al. Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 40, 9272–9285 (2012).
  CAS PubMed PubMed Central Google Scholar
• Thakur, B. K. et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 24, 766–769 (2014).
  CAS PubMed PubMed Central Google Scholar
• Kahlert, C. et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J. Biol. Chem. 289, 3869–3875 (2014).
  CAS PubMed PubMed Central Google Scholar
• Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980 (2013). This study shows that a ribonuclear sumoylated protein binds an RNA motif to promote the targeting of miRNA to exosomes.
  PubMed Google Scholar
• Mateescu, B. et al. Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper. J. Extracell. Vesicles 6, 1286095 (2017).
  PubMed PubMed Central Google Scholar
• Irion, U. & St Johnston, D. bicoid RNA localization requires specific binding of an endosomal sorting complex. Nature 445, 554–558 (2007).
  CAS PubMed PubMed Central Google Scholar
• Perez-Hernandez, D. et al. The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J. Biol. Chem. 288, 11649–11661 (2013).
  CAS PubMed PubMed Central Google Scholar
• Gibbings, D. J., Ciaudo, C., Erhardt, M. & Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nature Cell Biol. 11, 1143–1149 (2009).
  CAS PubMed Google Scholar
• McKenzie, A. J. et al. KRAS–MEK signaling controls Ago2 sorting into exosomes. Cell Rep. 15, 978–987 (2016).
  CAS PubMed PubMed Central Google Scholar
• Teng, Y. et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nat. Commun. 8, 14448 (2017).
  CAS PubMed PubMed Central Google Scholar
• Shurtleff, M. J., Temoche-Diaz, M. M., Karfilis, K. V., Ri, S. & Schekman, R. Y-Box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife 5, e19276 (2016).
  PubMed PubMed Central Google Scholar
• Carayon, K. et al. Proteolipidic composition of exosomes changes during reticulocyte maturation. J. Biol. Chem. 286, 34426–34439 (2011).
  CAS PubMed PubMed Central Google Scholar
• Segura, E., Amigorena, S. & Thery, C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells Mol. Dis. 35, 89–93 (2005).
  CAS PubMed Google Scholar
• Mobius, W. et al. Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J. Histochem. Cytochem. 50, 43–55 (2002).
  CAS PubMed Google Scholar
• van Niel, G. et al. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25, 885–894 (2006).
  CAS PubMed Google Scholar
• Edgar, J. R., Eden, E. R. & Futter, C. E. Hrs- and CD63-dependent competing mechanisms make different sized endosomal intraluminal vesicles. Traffic 15, 197–211 (2014).
  PubMed PubMed Central Google Scholar
• Hristov, M., Erl, W., Linder, S. & Weber, P. C. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood 104, 2761–2766 (2004).
  CAS PubMed Google Scholar
• Piccin, A., Murphy, W. G. & Smith, O. P. Circulating microparticles: pathophysiology and clinical implications. Blood Rev. 21, 157–171 (2007).
  CAS PubMed Google Scholar
• Jimenez, J. J. et al. Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb. Res. 109, 175–180 (2003).
  CAS PubMed Google Scholar
• Connor, D. E., Exner, T., Ma, D. D. & Joseph, J. E. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb. Haemost. 103, 1044–1052 (2010).
  CAS PubMed Google Scholar
• Del Conde, I., Shrimpton, C. N., Thiagarajan, P. & Lopez, J. A. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106, 1604–1611 (2005).
  CAS PubMed Google Scholar
• Li, B., Antonyak, M. A., Zhang, J. & Cerione, R. A. RhoA triggers a specific signaling pathway that generates transforming microvesicles in cancer cells. Oncogene 31, 4740–4749 (2012).
  CAS PubMed PubMed Central Google Scholar
• McConnell, R. E. et al. The enterocyte microvillus is a vesicle-generating organelle. J. Cell Biol. 185, 1285–1298 (2009).
  CAS PubMed PubMed Central Google Scholar
• Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956).
  CAS PubMed Google Scholar
• Wilson, K. F., Erickson, J. W., Antonyak, M. A. & Cerione, R. A. Rho GTPases and their roles in cancer metabolism. Trends Mol. Med. 19, 74–82 (2013).
  CAS PubMed Google Scholar
• Shen, B., Fang, Y., Wu, N. & Gould, S. J. Biogenesis of the posterior pole is mediated by the exosome/microvesicle protein-sorting pathway. J. Biol. Chem. 286, 44162–44176 (2011).
  CAS PubMed PubMed Central Google Scholar
• Yang, J. M. & Gould, S. J. The _cis_-acting signals that target proteins to exosomes and microvesicles. Biochem. Soc. Trans. 41, 277–282 (2013).
  CAS PubMed Google Scholar
• Bolukbasi, M. F. et al. miR-1289 and “zipcode”-like sequence enrich mRNAs in microvesicles. Mol. Ther. Nucleic Acids 1, e10 (2012).
  PubMed PubMed Central Google Scholar
• Mittelbrunn, M., Vicente-Manzanares, M. & Sanchez-Madrid, F. Organizing polarized delivery of exosomes at synapses. Traffic 16, 327–337 (2015).
  CAS PubMed PubMed Central Google Scholar
• Eitan, E., Suire, C., Zhang, S. & Mattson, M. P. Impact of lysosome status on extracellular vesicle content and release. Ageing Res. Rev. 32, 65–74 (2016).
  CAS PubMed PubMed Central Google Scholar
• Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011).
  CAS PubMed Google Scholar
• Villarroya-Beltri, C. et al. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat. Commun. 7, 13588 (2016).
  CAS PubMed PubMed Central Google Scholar
• Edgar, J. R., Manna, P. T., Nishimura, S., Banting, G. & Robinson, M. S. Tetherin is an exosomal tether. eLife 5, e17180 (2016). This study shows that exosomes can be released as clusters that remain attached to each other and anchored to the cell surface by tetherin. It suggests that the tetherin-mediated attachment may have a key role in exosome fate.
  PubMed PubMed Central Google Scholar
• Liegeois, S., Benedetto, A., Garnier, J. M., Schwab, Y. & Labouesse, M. The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans. J. Cell Biol. 173, 949–961 (2006).
  CAS PubMed PubMed Central Google Scholar
• Guix, F. X. et al. Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Mol. Neurodegener. 12, 25 (2017).
  PubMed PubMed Central Google Scholar
• van Niel, G., Porto-Carreiro, I., Simoes, S. & Raposo, G. Exosomes: a common pathway for a specialized function. J. Biochem. 140, 13–21 (2006).
  CAS PubMed Google Scholar
• Papandreou, M. E. & Tavernarakis, N. Autophagy and the endo/exosomal pathways in health and disease. Biotechnol. J. 12, 1600175 (2017).
  Google Scholar
• Dias, M. V. et al. PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy. Autophagy 12, 2113–2128 (2016).
  CAS PubMed PubMed Central Google Scholar
• Hessvik, N. P. et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell. Mol. Life Sci. 73, 4717–4737 (2016).
  CAS PubMed Google Scholar
• Bonifacino, J. S. & Glick, B. S. The mechanisms of vesicle budding and fusion. Cell 116, 153–166 (2004).
  CAS PubMed Google Scholar
• Cai, H., Reinisch, K. & Ferro-Novick, S. Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev.≈Cell 12, 671–682 (2007).
  CAS Google Scholar
• Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011).
  PubMed Google Scholar
• Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009).
  CAS PubMed PubMed Central Google Scholar
• Song, P., Trajkovic, K., Tsunemi, T. & Krainc, D. Parkin modulates endosomal organization and function of the endo-lysosomal pathway. J. Neurosci. 36, 2425–2437 (2016).
  CAS PubMed PubMed Central Google Scholar
• Mobius, W. et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic 4, 222–231 (2003).
  CAS PubMed Google Scholar
• Sinha, S. et al. Cortactin promotes exosome secretion by controlling branched actin dynamics. J. Cell Biol. 214, 197–213 (2016).
  CAS PubMed PubMed Central Google Scholar
• Marks, M. S., Heijnen, H. F. & Raposo, G. Lysosome-related organelles: unusual compartments become mainstream. Curr. Opin. Cell Biol. 25, 495–505 (2013).
  CAS PubMed PubMed Central Google Scholar
• Hsu, C. et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J. Cell Biol. 189, 223–232 (2010).
  CAS PubMed PubMed Central Google Scholar
• Savina, A., Furlan, M., Vidal, M. & Colombo, M. I. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J. Biol. Chem. 278, 20083–20090 (2003).
  CAS PubMed Google Scholar
• Jahn, R. & Scheller, R. H. SNAREs—engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631–643 (2006).
  CAS PubMed Google Scholar
• Rao, J. & Fitzpatrick, R. E. Use of the Q-switched 755-nm alexandrite laser to treat recalcitrant pigment after depigmentation therapy for vitiligo. Dermatol. Surg. 30, 1043–1045 (2004).
  PubMed Google Scholar
• Fader, C. M., Sánchez, D. G., Mestre, M. B. & Colombo, M. I. TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim. Biophys. Acta 1793, 1901–1916 (2009).
  CAS PubMed Google Scholar
• Proux-Gillardeaux, V., Raposo, G., Irinopoulou, T. & Galli, T. Expression of the Longin domain of TI-VAMP impairs lysosomal secretion and epithelial cell migration. Biol. Cell 99, 261–271 (2007).
  CAS PubMed Google Scholar
• Faure, J. et al. Exosomes are released by cultured cortical neurones. Mol. Cell Neurosci. 31, 642–648 (2006).
  CAS PubMed Google Scholar
• Raposo, G. et al. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol. Biol. Cell 8, 2631–2645 (1997).
  CAS PubMed PubMed Central Google Scholar
• Savina, A., Fader, C. M., Damiani, M. T. & Colombo, M. I. Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6, 131–143 (2005).
  CAS PubMed Google Scholar
• Puri, N. & Roche, P. A. Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms. Proc. Natl Acad. Sci. USA 105, 2580–2585 (2008).
  CAS PubMed PubMed Central Google Scholar
• Wei, Y. et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat. Commun. 8, 14041 (2017).
  CAS PubMed PubMed Central Google Scholar
• Gross, J. C., Chaudhary, V., Bartscherer, K. & Boutros, M. Active Wnt proteins are secreted on exosomes. Nat. Cell Biol. 14, 1036–1045 (2012).
  CAS PubMed Google Scholar
• Hyenne, V. et al. RAL-1 controls multivesicular body biogenesis and exosome secretion. J. Cell Biol. 211, 27–37 (2015).
  CAS PubMed PubMed Central Google Scholar
• Koles, K. & Budnik, V. Exosomes go with the Wnt. Cell Logist 2, 169–173 (2012).
  PubMed PubMed Central Google Scholar
• Matsumoto, A. et al. Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells. Cancer Sci. 108, 1803–1810 (2017).
  CAS PubMed PubMed Central Google Scholar
• D'Souza-Schorey, C. & Clancy, J. W. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 26, 1287–1299 (2012).
  CAS PubMed PubMed Central Google Scholar
• Sedgwick, A. E., Clancy, J. W., Olivia Balmert, M. & D'Souza-Schorey, C. Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion. Sci. Rep. 5, 14748 (2015).
  CAS PubMed PubMed Central Google Scholar
• Schlienger, S., Campbell, S. & Claing, A. ARF1 regulates the Rho/MLC pathway to control EGF-dependent breast cancer cell invasion. Mol. Biol. Cell 25, 17–29 (2014).
  PubMed PubMed Central Google Scholar
• Wehman, A. M., Poggioli, C., Schweinsberg, P., Grant, B. D. & Nance, J. The P4-ATPase TAT-5 inhibits the budding of extracellular vesicles in C. elegans embryos. Curr. Biol. 21, 1951–1959 (2011).
  CAS PubMed PubMed Central Google Scholar
• Taverna, S. et al. Shedding of membrane vesicles mediates fibroblast growth factor-2 release from cells. J. Biol. Chem. 278, 51911–51919 (2003).
  CAS PubMed Google Scholar
• Cocucci, E., Racchetti, G. & Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43–51 (2009).
  CAS PubMed Google Scholar
• Bianco, F. et al. Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J. Immunol. 174, 7268–7277 (2005).
  CAS PubMed Google Scholar
• Thomas, L. M. & Salter, R. D. Activation of macrophages by P2X7-induced microvesicles from myeloid cells is mediated by phospholipids and is partially dependent on TLR4. J. Immunol. 185, 3740–3749 (2010).
  CAS PubMed Google Scholar
• Bianco, F. et al. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 28, 1043–1054 (2009).
  CAS PubMed PubMed Central Google Scholar
• Mulcahy, L. A., Pink, R. C. & Carter, D. R. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).
  Google Scholar
• Denzer, K. et al. Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J. Immunol. 165, 1259–1265 (2000).
  CAS PubMed Google Scholar
• Mallegol, J. et al. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 132, 1866–1876 (2007).
  CAS PubMed Google Scholar
• Nolte-'t Hoen, E. N., Buschow, S. I., Anderton, S. M., Stoorvogel, W. & Wauben, M. H. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113, 1977–1981 (2009).
  CAS PubMed Google Scholar
• Chivet, M. et al. Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J. Extracell. Vesicles 3, 24722 (2014).
  PubMed Google Scholar
• Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015). This study shows for the first time that exosomal integrins have a key role in directing exosomes from cancer cells to particular organs and that this transfer induces metastasis.
  CAS PubMed PubMed Central Google Scholar
• Morelli, A. E. et al. Endocytosis, intracellular sorting and processing of exosomes by dendritic cells. Blood 104, 3257–3266 (2004).
  CAS PubMed Google Scholar
• Sung, B. H., Ketova, T., Hoshino, D., Zijlstra, A. & Weaver, A. M. Directional cell movement through tissues is controlled by exosome secretion. Nat. Commun. 6, 7164 (2015).
  CAS PubMed Google Scholar
• Purushothaman, A. et al. Fibronectin on the surface of myeloma cell-derived exosomes mediates exosome-cell interactions. J. Biol. Chem. 291, 1652–1663 (2016).
  CAS PubMed Google Scholar
• Leiss, M., Beckmann, K., Giros, A., Costell, M. & Fassler, R. The role of integrin binding sites in fibronectin matrix assembly in vivo. Curr. Opin. Cell Biol. 20, 502–507 (2008).
  CAS PubMed Google Scholar
• Rana, S., Yue, S., Stadel, D. & Zoller, M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int. J. Biochem. Cell Biol. 44, 1574–1584 (2012).
  CAS PubMed Google Scholar
• Nazarenko, I. et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 70, 1668–1678 (2010).
  CAS PubMed Google Scholar
• Rana, S., Claas, C., Kretz, C. C., Nazarenko, I. & Zoeller, M. Activation-induced internalization differs for the tetraspanins CD9 and Tspan8: Impact on tumor cell motility. Int. J. Biochem. Cell Biol. 43, 106–119 (2011).
  CAS PubMed Google Scholar
• Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015).
  CAS PubMed PubMed Central Google Scholar
• Bruno, S. et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J. Am. Soc. Nephrol. 20, 1053–1067 (2009).
  CAS PubMed PubMed Central Google Scholar
• Barres, C. et al. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115, 696–705 (2010).
  CAS PubMed Google Scholar
• Frey, B. & Gaipl, U. S. The immune functions of phosphatidylserine in membranes of dying cells and microvesicles. Semin. Immunopathol. 33, 497–516 (2011).
  CAS PubMed Google Scholar
• Feng, D. et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic 11, 675–687 (2010).
  CAS PubMed Google Scholar
• Nakase, I., Kobayashi, N. B., Takatani-Nakase, T. & Yoshida, T. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci. Rep. 5, 10300 (2015).
  CAS PubMed PubMed Central Google Scholar
• Tian, T. et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 289, 22258–22267 (2014).
  CAS PubMed PubMed Central Google Scholar
• Laulagnier, K. et al. Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons. Cell. Mol. Life Sci. http://dx.doi.org/10.1007/s00018-017-2664-0 (2017).
• Vargas, A. et al. Syncytin proteins incorporated in placenta exosomes are important for cell uptake and show variation in abundance in serum exosomes from patients with preeclampsia. FASEB J. 28, 3703–3719 (2014).
  CAS PubMed Google Scholar
• Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).
  CAS PubMed PubMed Central Google Scholar
• Prada, I. et al. A new approach to follow a single extracellular vesicle-cell interaction using optical tweezers. Biotechniques 60, 35–41 (2016).
  CAS PubMed Google Scholar
• Heusermann, W. et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J. Cell Biol. 213, 173–184 (2016).
  CAS PubMed PubMed Central Google Scholar
• Escrevente, C., Keller, S., Altevogt, P. & Costa, J. Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer 11, 108 (2011).
  CAS PubMed PubMed Central Google Scholar
• Chen, W. et al. Nanoscale characterization of carrier dynamic and surface passivation in InGaN/GaN multiple quantum wells on GaN nanorods. ACS Appl. Mater. Interfaces 8, 31887–31893 (2016).
  CAS PubMed Google Scholar
• Tian, T., Wang, Y., Wang, H., Zhu, Z. & Xiao, Z. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J. Cell. Biochem. 111, 488–496 (2010).
  CAS PubMed Google Scholar
• Bissig, C. & Gruenberg, J. ALIX and the multivesicular endosome: ALIX in Wonderland. Trends Cell Biol. 24, 19–25 (2014).
  CAS PubMed Google Scholar
• Antonyak, M. A. et al. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc. Natl Acad. Sci. USA 108, 4852–4857 (2011).
  CAS PubMed PubMed Central Google Scholar
• Desrochers, L. M., Bordeleau, F., Reinhart-King, C. A., Cerione, R. A. & Antonyak, M. A. Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat. Commun. 7, 11958 (2016).
  CAS PubMed PubMed Central Google Scholar
• Zhang, L. & Wrana, J. L. The emerging role of exosomes in Wnt secretion and transport. Curr. Opin. Genet. Dev. 27, 14–19 (2014).
  PubMed Google Scholar
• Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).
  CAS PubMed PubMed Central Google Scholar
• Record, M., Carayon, K., Poirot, M. & Silvente-Poirot, S. Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim. Biophys. Acta 1841, 108–120 (2014).
  CAS PubMed Google Scholar
• Coleman, B. M. & Hill, A. F. Extracellular vesicles—their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin. Cell Dev. Biol. 40, 89–96 (2015).
  CAS PubMed Google Scholar
• van Dongen, H. M., Masoumi, N., Witwer, K. W. & Pegtel, D. M. Extracellular vesicles exploit viral entry routes for cargo delivery. Microbiol. Mol. Biol. Rev. 80, 369–386 (2016).
  CAS PubMed PubMed Central Google Scholar
• Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016).
  PubMed PubMed Central Google Scholar
• Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).
  CAS PubMed Google Scholar
• Fais, S. et al. Evidence-based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 10, 3886–3899 (2016).
  CAS PubMed Google Scholar
• Dinkins, M. B., Dasgupta, S., Wang, G., Zhu, G. & Bieberich, E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol. Aging 35, 1792–1800 (2014).
  CAS PubMed PubMed Central Google Scholar
• Torrano, V. et al. Vesicle-MaNiA: extracellular vesicles in liquid biopsy and cancer. Curr. Opin. Pharmacol. 29, 47–53 (2016).
  CAS PubMed PubMed Central Google Scholar
• El Andaloussi, S., Lakhal, S., Mager, I. & Wood, M. J. Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 65, 391–397 (2013).
  CAS PubMed Google Scholar
• Pitt, J. M. et al. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J. Immunol. 193, 1006–1011 (2014).
  CAS PubMed Google Scholar
• Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5, e1071008 (2016).
  PubMed Google Scholar
• Lener, T. et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J. Extracell. Vesicles 4, 30087 (2015).
  PubMed Google Scholar
• Lo Cicero, A. et al. Exosomes released by keratinocytes modulate melanocyte pigmentation. Nat. Commun. 6, 7506 (2015).
  CAS PubMed Google Scholar
• Beauvillain, C., Juste, M. O., Dion, S., Pierre, J. & Dimier-Poisson, I. Exosomes are an effective vaccine against congenital toxoplasmosis in mice. Vaccine 27, 1750–1757 (2009).
  CAS PubMed Google Scholar
• Ranghino, A. et al. The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury. Stem Cell Res. Ther. 8, 24 (2017).
  PubMed PubMed Central Google Scholar
• Arslan, F. et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 10, 301–312 (2013).
  CAS PubMed Google Scholar
• Ophelders, D. R. et al. Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med. 5, 754–763 (2016).
  CAS PubMed PubMed Central Google Scholar
• Mizrak, A. et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol. Ther. 21, 101–108 (2013).
  CAS PubMed Google Scholar
• Pan, S., Yang, X., Jia, Y., Li, R. & Zhao, R. Microvesicle-shuttled miR-130b reduces fat deposition n recipient primary cultured porcine adipocytes by inhibiting PPAR-g expression. J. Cell. Physiol. 229, 631–639 (2014).
  CAS PubMed Google Scholar
• Coumans, F. A. W. et al. Methodological guidelines to study extracellular vesicles. Circ. Res. 120, 1632–1648 (2017).
  CAS PubMed Google Scholar
• Van Deun, J. et al. EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods 14, 228–232 (2017).
  CAS PubMed Google Scholar
• Takov, K., Yellon, D. M. & Davidson, S. M. Confounding factors in vesicle uptake studies using fluorescent lipophilic membrane dyes. J. Extracell. Vesicles 6, 1388731 (2017).
  PubMed PubMed Central Google Scholar
• Hyenne, V., Lefebvre, O. & Goetz, J. G. Going live with tumor exosomes and microvesicles. Cell Adh. Migr. 11, 173–186 (2017).
  CAS PubMed PubMed Central Google Scholar
• Lai, C. P., Tannous, B. A. & Breakefield, X. O. Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol. Biol. 1098, 249–258 (2014).
  CAS PubMed PubMed Central Google Scholar
• Zomer, A. et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161, 1046–1057 (2015). This study uses in vivo imaging to reveal the existence of a functional transfer of mRNA mediated by extracellular vesicles in the context of cancer and metastasis.
  CAS PubMed PubMed Central Google Scholar
• Bobrie, A., Colombo, M., Krumeich, S., Raposo, G. & Thery, C. Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J. Extracell. Vesicles 1, 18397 (2012).
  CAS Google Scholar
• Roucourt, B., Meeussen, S., Bao, J., Zimmermann, P. & David, G. Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res. 25, 412–428 (2015).
  CAS PubMed PubMed Central Google Scholar
• van Niel, G. et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology 121, 337–349 (2001).
  CAS PubMed Google Scholar
• Tauro, B. J. et al. Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Mol. Cell. Proteomics 12, 587–598 (2013).
  CAS PubMed Google Scholar