Innovation | Published:

Extracellular vesicles: biology and emerging therapeutic opportunities

Nature Reviews Drug Discovery volume 12, pages 347357 (2013) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum. Mol. Genet. 21, R125–R134 (2012).

  2. 2.

    & Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).

  3. 3.

    , & 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).

  4. 4.

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

  5. 5.

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

  6. 6.

    , & Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med. 6, 481–492 (2011).

  7. 7.

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

  8. 8.

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

  9. 9.

    , , & Primary human keratinocytes externalize stratifin protein via exosomes. J. Cell. Biochem. 104, 2165–2173 (2008).

  10. 10.

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

  11. 11.

    , , & Astrocytes and glioblastoma cells release exosomes carrying mtDNA. J. Neural Transm. 117, 1–4 (2010).

  12. 12.

    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).

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

    , , , & Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc. Natl Acad. Sci. USA 106, 3794–3799 (2009).

  17. 17.

    , & Exosomes: immune properties and potential clinical implementations. Semin. Immunopathol. 33, 419–459 (2011).

  18. 18.

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

  19. 19.

    & Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol. Mol. Biol. Rev. 74, 81–94 (2010).

  20. 20.

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

  21. 21.

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

  22. 22.

    , , & Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12, 1659–1668 (2011).

  23. 23.

    , & Membrane vesicles as conveyors of immune responses. Nature Rev. Immunol. 9, 581–593 (2009).

  24. 24.

    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).

  25. 25.

    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).

  26. 26.

    , , & Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106, 1604–1611 (2005).

  27. 27.

    & Extracellular vesicles — vehicles that spread cancer genes. Bioessays 34, 489–497 (2012).

  28. 28.

    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).

  29. 29.

    , , & Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front. Physiol. 3, 124 (2012).

  30. 30.

    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).

  31. 31.

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

  32. 32.

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

  33. 33.

    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).

  34. 34.

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

  35. 35.

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

  36. 36.

    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).

  37. 37.

    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).

  38. 38.

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

  39. 39.

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

  40. 40.

    , , , & 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).

  41. 41.

    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).

  42. 42.

    , , , & Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).

  43. 43.

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

  44. 44.

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

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 48.

    , , , & Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol. Lett. 113, 76–82 (2007).

  49. 49.

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

  50. 50.

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

  51. 51.

    , , , & Emerging role of neuronal exosomes in the central nervous system. Front. Physiol. 3, 145 (2012).

  52. 52.

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

  53. 53.

    , , , & Hematopoietic stem cells convert into liver cells within days without fusion. Nature Cell Biol. 6, 532–539 (2004).

  54. 54.

    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).

  55. 55.

    & Cellular phenotype switching and microvesicles. Adv. Drug Deliv. Rev. 62, 1141–1148 (2010).

  56. 56.

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

  57. 57.

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

  58. 58.

    , , , & The microvesicle as a vehicle for EMMPRIN in tumor–stromal interactions. Oncogene 23, 956–963 (2004).

  59. 59.

    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).

  60. 60.

    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).

  61. 61.

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

  62. 62.

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

  63. 63.

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

  64. 64.

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

  65. 65.

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

  66. 66.

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

  67. 67.

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

  68. 68.

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

  69. 69.

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

  70. 70.

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

  71. 71.

    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).

  72. 72.

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

  73. 73.

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

  74. 74.

    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).

  75. 75.

    , , & Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6, 131–143 (2005).

  76. 76.

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

  77. 77.

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

  78. 78.

    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).

  79. 79.

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

  80. 80.

    & Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front. Physiol. 3, 228 (2012).

  81. 81.

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

  82. 82.

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

  83. 83.

    , , , & Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol. Dial. Transplant. 27, 3037–3042 (2012).

  84. 84.

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

  85. 85.

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

  86. 86.

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

  87. 87.

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

  88. 88.

    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).

  89. 89.

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

  90. 90.

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

  91. 91.

    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).

  92. 92.

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

  93. 93.

    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).

  94. 94.

    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).

  95. 95.

    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).

  96. 96.

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

  97. 97.

    , , , & Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE 5, e11469 (2010).

  98. 98.

    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).

  99. 99.

    & Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 26, 1287–1299 (2012).

  100. 100.

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

  101. 101.

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

  102. 102.

    , , & Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nature Cell Biol. 11, 1143–1149 (2009).

  103. 103.

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

  104. 104.

    , , & Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 65, 391–397 (2013).

  105. 105.

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

  106. 106.

    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).

  107. 107.

    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).

  108. 108.

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

  109. 109.

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

  110. 110.

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

  111. 111.

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

  112. 112.

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

  113. 113.

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

  114. 114.

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

  115. 115.

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

  116. 116.

    , , , & 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).

  117. 117.

    , , & Active Wnt proteins are secreted on exosomes. Nature Cell Biol. 14, 1036–1045 (2012).

  118. 118.

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

  119. 119.

    , , & Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 1 Apr 2006 (10.1002/0471143030.cb0322s30).

  120. 120.

    , , & Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnol. Adv. 25 Aug 2012 (10.1016/j.biotechadv.2012.08.008).

Download references

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.

Author information

Affiliations

  1. Samir EL Andaloussi, Imre Mäger and Matthew J. A. Wood are at the Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.

    • Samir EL Andaloussi
    • , Imre Mäger
    •  & Matthew J. A. Wood
  2. Xandra O. Breakefield is at the Massachusetts General Hospital, Neurogenetics Unit, Charlestown, Massachusetts 2129, USA.

    • Xandra O. Breakefield
  3. Samir EL Andaloussi is also at the Department of Laboratory Medicine, Karolinska Institutet, Hälsov. 7, Solna SE-141 86, Sweden.

    • Samir EL Andaloussi
  4. Imre Mäger is also at the Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.

    • Imre Mäger

Authors

  1. Search for Samir EL Andaloussi in:

  2. Search for Imre Mäger in:

  3. Search for Xandra O. Breakefield in:

  4. Search for Matthew J. A. Wood in:

Competing interests

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.

Corresponding author

Correspondence to Matthew J. A. Wood.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrd3978

Further reading