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Extracellular vesicles: biology and emerging therapeutic opportunities

Abstract

Within the past decade, extracellular vesicles have emerged as important mediators of intercellular communication, being involved in the transmission of biological signals between cells in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. In addition, pathophysiological roles for extracellular vesicles are beginning to be recognized in diseases including cancer, infectious diseases and neurodegenerative disorders, highlighting potential novel targets for therapeutic intervention. Moreover, both unmodified and engineered extracellular vesicles are likely to have applications in macromolecular drug delivery. Here, we review recent progress in understanding extracellular vesicle biology and the role of extracellular vesicles in disease, discuss emerging therapeutic opportunities and consider the associated challenges.

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Figure 1: Biogenesis of extracellular vesicles and their interactions with recipient cells.
Figure 2: Roles of extracellular vesicles in normal physiology and disease pathogenesis.
Figure 3: Therapeutic targeting and exploitation of extracellular vesicles.

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References

  1. Lee, Y., El Andaloussi, S. & Wood, M. J. A. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum. Mol. Genet. 21, R125–R134 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Pan, B. T. & Johnstone, R. M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Ratajczak, J. et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20, 847–856 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Camussi, G. et al. Exosome/microvesicle-mediated epigenetic reprogramming of cells. Am. J. Cancer Res. 1, 98–110 (2011).

    PubMed  Google Scholar 

  6. Lai, R. C., Chen, T. S. & Lim, S. K. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med. 6, 481–492 (2011).

    Article  PubMed  Google Scholar 

  7. Timmers, L. et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res. 6, 206–214 (2011).

    Article  PubMed  Google Scholar 

  8. Timmers, L. et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 1, 129–137 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Chavez-Muñoz, C., Morse, J., Kilani, R. & Ghahary, A. Primary human keratinocytes externalize stratifin protein via exosomes. J. Cell. Biochem. 104, 2165–2173 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Faure, J. et al. Exosomes are released by cultured cortical neurones. Mol. Cell. Neurosci. 31, 642–648 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Guescini, M., Genedani, S., Stocchi, V. & Agnati, L. F. Astrocytes and glioblastoma cells release exosomes carrying mtDNA. J. Neural Transm. 117, 1–4 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Kesimer, M. et al. Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J. 23, 1858–1868 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Potolicchio, A. et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 175, 2237–2243 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Al-Nedawi, K. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nature Cell Biol. 10, 619–624 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature Cell Biol. 10, 1470–1476 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Al-Nedawi, K., Meehan, B., Kerbel, R. S., Allison, A. C. & Rak, J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc. Natl Acad. Sci. USA 106, 3794–3799 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chaput, N., Théry, C. & Thery, C. Exosomes: immune properties and potential clinical implementations. Semin. Immunopathol. 33, 419–459 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Chatterjee, S. N. & Das, J. Electron microscopic observations on the excretion of cell-wall material by Vibrio cholerae. J. Gen. Microbiol. 49, 1–11 (1967).

    Article  CAS  PubMed  Google Scholar 

  19. Ellis, T. N. & Kuehn, M. J. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol. Mol. Biol. Rev. 74, 81–94 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Beveridge, T. J. Structures of gram-negative cell walls and their derived membrane vesicles. J. Bacteriol. 181, 4725–4733 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Bobrie, A., Colombo, M., Raposo, G. & Thery, C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12, 1659–1668 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Théry, C., Ostrowski, M. & Segura, E. Membrane vesicles as conveyors of immune responses. Nature Rev. Immunol. 9, 581–593 (2009).

    Article  CAS  Google Scholar 

  24. Ratajczak, M. Z. et al. Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? Leukemia 26, 1166–1173 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Gatti, S. et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol. Dial. Transplant. 26, 1474–1483 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Del Conde, I., Shrimpton, C. N., Thiagarajan, P. & López, J. A. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106, 1604–1611 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Rak, J. & Guha, A. Extracellular vesicles — vehicles that spread cancer genes. Bioessays 34, 489–497 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Mack, M. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nature Med. 6, 769–775 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Bellingham, S. A., Guo, B. B., Coleman, B. M. & Hill, A. F. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front. Physiol. 3, 124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Emmanouilidou, E. et al. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838–6851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vella, L. J. et al. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 211, 582–590 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nature Med. 4, 594–600 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Wahlgren, J. et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40, e130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotech. 29, 341–345 (2011).

    Article  CAS  Google Scholar 

  36. Zhuang, X. et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19, 1769–1779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, D. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606–1614 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Baietti, M. F. et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nature Cell Biol. 14, 677–685 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. 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, 4146–4197 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Baj-Krzyworzeka, M. et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol. Immunother. 55, 808–818 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Clayton, A., Mitchell, J. P., Court, J., Mason, M. D. & Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Clayton, A. et al. Human tumor-derived exosomes down-modulate NKG2D expression. J. Immunol. 180, 7249–7258 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Liu, C. et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J. Immunol. 176, 1375–1385 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Yu, S. et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J. Immunol. 178, 6867–6875 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Eken, C. et al. Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J. Immunol. 180, 817–824 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Baj-Krzyworzeka, M. et al. Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp. Hematol. 30, 450–459 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Baj-Krzyworzeka, M., Szatanek, R., Weglarczyk, K., Baran, J. & Zembala, M. Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol. Lett. 113, 76–82 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Sprague, D. L. et al. Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 111, 5028–5036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Simhadri, V. R. et al. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS ONE 3, e3377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chivet, M., Hemming, F., Pernet-Gallay, K., Fraboulet, S. & Sadoul, R. Emerging role of neuronal exosomes in the central nervous system. Front. Physiol. 3, 145 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lachenal, G. et al. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol. Cell. Neurosci. 46, 409–418 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Jang, Y.-Y., Collector, M. I., Baylin, S. B., Diehl, A. M. & Sharkis, S. J. Hematopoietic stem cells convert into liver cells within days without fusion. Nature Cell Biol. 6, 532–539 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Aliotta, J. M. et al. Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells 25, 2245–2256 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Quesenberry, P. J. & Aliotta, J. M. Cellular phenotype switching and microvesicles. Adv. Drug Deliv. Rev. 62, 1141–1148 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Aliotta, J. M. et al. Stable cell fate changes in marrow cells induced by lung-derived microvesicles. J. Extracellular Vesicles 1, 18163 (2012).

    Article  CAS  Google Scholar 

  57. Peinado, H. H. H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Med. 18, 883–891 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Sidhu, S. S., Mengistab, A. T., Tauscher, A. N., LaVail, J. & Basbaum, C. The microvesicle as a vehicle for EMMPRIN in tumor–stromal interactions. Oncogene 23, 956–963 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Wieckowski, E. U. et al. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J. Immunol. 183, 3720–3730 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, J. W. et al. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin. Cancer Res. 11, 1010–1020 (2005).

    CAS  PubMed  Google Scholar 

  61. Cai, Z. et al. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J. Immunol. 188, 5954–5961 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Dvorak, H. F. et al. Tumor shedding and coagulation. Science 212, 923–924 (1981).

    Article  CAS  PubMed  Google Scholar 

  63. Tesselaar, M. E. T. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J. Thromb. Haemost. 5, 520–527 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Millimaggi, D. et al. Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia 9, 349–357 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sheldon, H. et al. New mechanism for Notch signaling to endothelium at a distance by δ-like 4 incorporation into exosomes. Blood 116, 2385–2394 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Yang, M. et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol. Cancer 10, 117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pegtel, D. M. et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad. Sci. USA 107, 6328–6333 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Logozzi, M. et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4, e5219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sverdlov, E. D. Amedeo Avogadro's cry: what is 1 μg of exosomes? Bioessays 34, 873–875 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Chalmin, F. et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457–471 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Nazarenko, I. et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 70, 1668–1678 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biol. 12, 19–30 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Bobrie, A. et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 72, 4920–4930 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. Hsu, C. et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J. Cell Biol. 189, 223–232 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lima, L. G. et al. Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett. 283, 168–175 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Deregibus, M. C. et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110, 2440–2448 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Herrera, M. B. et al. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J. Cell. Mol. Med. 14, 1605–1618 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Lai, C. P.-K. & Breakefield, X. O. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front. Physiol. 3, 228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature Med. 11, 367–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Biancone, L., Bruno, S., Deregibus, M. C., Tetta, C. & Camussi, G. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol. Dial. Transplant. 27, 3037–3042 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Bruno, S. et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J. Am. Soc. Nephrol. 20, 1053–1067 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lai, R. C. et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4, 214–222 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Bruno, S. et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE 7, e33115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yeo, R. W. Y. et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv. Drug Deliv. Rev. 65, 336–341 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Cantaluppi, V. et al. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia–reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 82, 412–427 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Cantaluppi, V. et al. Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets. Cell Transplant. 21, 1305–1320 (2012).

    Article  PubMed  Google Scholar 

  90. Lamparski, H. G. et al. Production and characterization of clinical grade exosomes derived from dendritic cells. J. Immunol. Methods 270, 211–226 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Chen, T. S. et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J. Transl. Med. 9, 47 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bhatnagar, S. & Schorey, J. S. Exosomes released from infected macrophages contain mycobacterium avium glycopeptidolipids and are proinflammatory. J. Biol. Chem. 282, 25779–25789 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Vega, V. L. et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J. Immunol. 180, 4299–4307 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Gastpar, R. et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65, 5238–5247 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Monleón, I. et al. Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J. Immunol. 167, 6736–6744 (2001).

    Article  PubMed  Google Scholar 

  96. Kim, S.-H. H. et al. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J. Immunol. 174, 6440–6448 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Szajnik, M., Czystowska, M., Szczepanski, M. J., Mandapathil, M. & Whiteside, T. L. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE 5, e11469 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Collino, F. et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS ONE 5, e11803 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nature Commun. 2, 282 (2011).

    Article  CAS  Google Scholar 

  101. Montecalvo, A. et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119, 756–766 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. El Andaloussi, S., Lakhal, S., Mäger, I. & Wood, M. J. A. Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 65, 391–397 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Akao, Y. et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol. Ther. 19, 395–399 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Pan, Q. et al. Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). Gut 61, 1330–1339 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Olson, S. D. et al. Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington's disease affected neuronal cells for reduction of huntingtin. Mol. Cell. Neurosci. 49, 271–281 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Lentz, T. L. Rabies virus binding to an acetylcholine receptor α-subunit peptide. J. Mol. Recognit. 3, 82–88 (1990).

    Article  CAS  PubMed  Google Scholar 

  109. Maguire, C. A. et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol. Ther. 20, 960–971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bolukbasi, M. F. et al. miR-1289 and “zipcode”-like sequence enrich mRNAs in microvesicles. Mol. Ther. Nucleic Acids 1, e10 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mizrak, A. et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol. Ther. 21, 101–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ohno, S. et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21, 185–191 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhu, W. et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 315, 28–37 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Bruno, S. et al. Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev. 22, 758–771 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. De Jong, O. G. et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J. Extracellular Vesicles 1, 18396 (2012).

    Article  CAS  Google Scholar 

  116. Hedlund, M., Nagaeva, O., Kargl, D., Baranov, V. & Mincheva-Nilsson, L. Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS ONE 6, e16899 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gross, J. C., Chaudhary, V., Bartscherer, K. & Boutros, M. Active Wnt proteins are secreted on exosomes. Nature Cell Biol. 14, 1036–1045 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Muralidharan-Chari, V. et al. ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875–1885 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Théry, C., Amigorena, S., Raposo, G. & Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 1 Apr 2006 (10.1002/0471143030.cb0322s30).

  120. Lai, R. C., Yeo, R. W. Y., Tan, K. H. & Lim, S. K. Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnol. Adv. 25 Aug 2012 (10.1016/j.biotechadv.2012.08.008).

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Acknowledgements

S.E.A. is supported by a postdoctoral research fellowship from the Swedish Society of Medical Research (SSMF) and the Swedish Medical Research Council (VR-med unga forskare). I.M. is supported by a Postdoctoral MOBILITAS Fellowship of the Estonian Science Foundation.

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Correspondence to Matthew J. A. Wood.

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Matthew J. A. Wood and Samir EL Andaloussi have filed patent applications in relation to extracellular vesicles. Patents filed are as follows: WO2010/119256, priority date April 2009; UK1121070.5 and UK1121069.7, filed December 2011.

Xandra O. Breakefield is on the Scientific Advisory Board for Exosome Diagnostics.

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EL Andaloussi, S., Mäger, I., Breakefield, X. et al. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12, 347–357 (2013). https://doi.org/10.1038/nrd3978

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