Skip to main content

Extracellular vesicles: fundamentals and clinical relevance

Abstract

All types of cells of eukaryotic organisms produce and release small nanovesicles into their extracellular environment. Early studies have described these vesicles as ‘garbage bags’ only to remove obsolete cellular molecules. Valadi and colleagues, in 2007, were the first to discover the capability of circulating extracellular vesicles (EVs) to horizontally transfer functioning gene information between cells. These extracellular vesicles express components responsible for angiogenesis promotion, stromal remodeling, chemoresistance, genetic exchange, and signaling pathway activation through growth factor/receptor transfer. EVs represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, signaling proteins, and RNAs. They contribute to physiology and pathology, and they have a myriad of potential clinical applications in health and disease. Moreover, vesicles can pass the blood–brain barrier and may perhaps even be considered as naturally occurring liposomes. These cell-derived EVs not only represent a central mediator of the disease microenvironment, but their presence in the peripheral circulation may serve as a surrogate for disease biopsies, enabling real-time diagnosis and disease monitoring. In this review, we’ll be addressing the characteristics of different types of extracellular EVs, as well as their clinical relevance and potential as diagnostic markers, and also define therapeutic options.

References

  1. Valadi H. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9:654–659.

    CAS  PubMed  Google Scholar 

  2. Bellingham SA, Hill AF. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?. Front Physiol 2012; 3:124.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res 2008; 7:5157–5166.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Morel O, Jesel L, Freyssinet JM, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31:15–26.

    CAS  PubMed  Google Scholar 

  5. Yuana Y, Oosterkamp TH, Bahatyrova S, Ashcroft B, Garcia Rodriguez P, Bertina RM, Osanto S. Atomic force microscopy: a novel approach to the detection of nanosized blood microparticles. J Thromb Haemost 2010; 8:315–323.

    CAS  PubMed  Google Scholar 

  6. Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJ, Hole P, et al. Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomedicine 2011; 7:780–788.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. E van der Pol, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev 2012; 64:676–705.

    PubMed  Google Scholar 

  8. Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9:581–593.

    PubMed  Google Scholar 

  9. Beyer C, Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol 2010; 6:21–29.

    CAS  PubMed  Google Scholar 

  10. Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics 2010; 73:1907–1920.

    CAS  PubMed  Google Scholar 

  11. Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012; 21:R125–R134.

    CAS  PubMed  Google Scholar 

  12. Bobrie A, Colombo M, Raposo G, The´ry C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 2011; 12:1659–1668.

    CAS  PubMed  Google Scholar 

  13. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigenpresenting vesicles. J Exp Med 1996; 183:1161–1172.

    CAS  PubMed  Google Scholar 

  14. Aalberts M, van Dissel-Emiliani FM, van Adrichem NP, van Wijnen M, Wauben MH, Stout TA, Stoorvogel W. Identification of distinct populations of prostasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans. Biol Reprod 2012; 86:82.

    PubMed  Google Scholar 

  15. Rana S, Yue S, Stadel D, Zöller M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 2012; 44:1574–1584.

    CAS  PubMed  Google Scholar 

  16. Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 2014; 3:24641.

    Google Scholar 

  17. Corrado C, Raimondo S, Chiesi A, Ciccia F, DeLeo G, Alessandro R. Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 2013; 14:5338–5366.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Caby MP, Lankar D, Vincendeau C-Scherrer, Raposo G, Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol 2005; 17:879–887.

    CAS  PubMed  Google Scholar 

  19. Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA 2004; 101:13368–13373.

    CAS  PubMed  Google Scholar 

  20. Ogawa Y, Miura Y, Harazono A, Kanai-Azuma M, Akimoto Y, Kawakami H, et al. Proteomic analysis of two types of exosomes in human whole saliva. Biol Pharm Bull 2011; 34:13–23.

    CAS  PubMed  Google Scholar 

  21. Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol 2008; 79:12–17.

    CAS  PubMed  Google Scholar 

  22. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002; 360:295–305.

    CAS  PubMed  Google Scholar 

  23. Masyuk AI, Huang BQ, Ward CJ, Gradilone SA, Banales JM, Masyuk TV, et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol 2010; 299:G990–G999.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kang D, Oh S, Ahn SM, Lee BH, Moon MH. Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nano-flow liquid chromatography-tandem mass spectrometry. J Proteome Res 2008; 7:3475–3480.

    CAS  PubMed  Google Scholar 

  25. DD Taylor, C Gercel-Taylor. The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids. Front Genet 2013; 4:142,

    PubMed  PubMed Central  Google Scholar 

  26. Kang D, Oh S, Ahn SM, Lee BH, Moon MH. Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nano flow liquid chromatography-tandem mass spectrometry. J Proteome Res 2008; 7:3475–3480.

    CAS  PubMed  Google Scholar 

  27. Soo CY, Song Y, Zheng Y, Campbell EC, Riches AC, Gunn-Moore F, Powis SJ. Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells. Immunology 2012; 136:192–197.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nolte-’t Hoen EN, van der Vlist EJ, Aalberts M, Mertens HC, Bosch BJ, Bartelink W, et al. Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles. Nanomedicine 2012b; 8:712–720.

    PubMed  Google Scholar 

  29. van der Vlist EJ, EN Nolte-’t Hoen, Stoorvogel W, Arkesteijn GJ, Wauben MH. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nat Protoc 2012; 7:1311–1326.

    PubMed  Google Scholar 

  30. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200:373–383.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006; 20:1487–1495.

    CAS  PubMed  Google Scholar 

  32. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9:654–659.

    CAS  PubMed  Google Scholar 

  33. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MA, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2011; 2:282.

    PubMed  PubMed Central  Google Scholar 

  34. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 2012; 119:756–766.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bellingham SA, Coleman BM, Hill AF. Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res 2012; 40:10937–10949.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nolte-’t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, PA ’t Hoen. 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 2012a; 40:9272–9285.

    PubMed  PubMed Central  Google Scholar 

  37. Camussi G, PJ. Quesenberry. Perspectives on the potential therapeutic uses of vesicles. Exosomes Microvesicles 2013; 1:6.

    Google Scholar 

  38. Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 2012; 10:e1001450.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Valapala M, Vishwanatha JK. Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2. J Biol Chem 2011; 286:30911–30925.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kober L, Zehe C, Bode J. Development of a novel ER stress based selection system for the isolation of highly productive clones. Biotechnol Bioeng 2012; 109:2599–2611.

    CAS  PubMed  Google Scholar 

  41. Gercel-Taylor C, Tullis RH, Atay S, Kesimer M, Taylor DD. Nano particle analysis of circulating cell-derived vesicles in ovarian cancer patients. Anal Biochem 2012; 428:44–53.

    CAS  PubMed  Google Scholar 

  42. Ji H, Greening DW, Barnes TW, Lim JW, Tauro BJ, Rai A, et al. Proteome profiling of exosomes derived from human primary and metastatic colorectal cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 2013; 13:1672–1686.

    CAS  PubMed  Google Scholar 

  43. Whiteside TL. Immune modulation of T-cell and NK (natural killer)cell activities by TEXs (tumour derived exosomes). Biochem Soc Trans 2013; 41:245–251.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ivannikov M, et al. Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume. J Mol Neurosci 2013; 49:223–230.

    CAS  PubMed  Google Scholar 

  45. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009; 284:34211–34222.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Atay S, Gercel-Taylor C, Kesimer M, Taylor DD. Morphologic and proteomic characterization of exosomes released by cultured extravillous trophoblast cells. Exp Cell Res 2011a; 317:1192–1202.

    CAS  PubMed  Google Scholar 

  47. Frangsmyr L, Baranov V, Nagaeva O, Stendahl U, Kjellberg L, Mincheva-Nilsson L. Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level. Mol Hum Reprod 2005; 11:35–41.

    CAS  PubMed  Google Scholar 

  48. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 2008; 180:7249–7258.

    CAS  PubMed  Google Scholar 

  49. Andaloussi I Mager SEL, Breakfield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013; 12:347–357.

    PubMed  Google Scholar 

  50. Rautou PE, Leroyer AS, Ramkhelawon B, Devue C, Duflaut D, Vion AC, et al. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ Res 2011; 108:335–343.

    CAS  PubMed  Google Scholar 

  51. Zhao Y, Jiang Z, Guo C. New hope for type 2 diabetics: Targeting insulin resistance through the immune modulation of stem cells. Autoimmun Rev 2011; 11:137–142.

    CAS  PubMed  Google Scholar 

  52. Fafi-Kremer S, et al. Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation. J Exp Med 2010; 207:2019–2031.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Barsoum RS. Hepatitis C virus: from entry to renal injury — facts and potentials. Nephrol Dial Transplant 2007; 22:1840–1848.

    PubMed  Google Scholar 

  54. Feng Z, et al. A pathogenic picornavirus acquires an envelope by hijacking cellular membranes. Nature 2013; 496:367–371.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 2010; 107:6328–6333.

    CAS  PubMed  Google Scholar 

  56. Meckes DG Jr, Raab-Traub N. Microvesicles and viral infection. J Virol 2011; 85:12844–12854.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Corrado C, Raimondo S, Chiesi A, Ciccia F, Leo De G, Alessandro R. Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 2013; 14:5338–5366.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Demirovic D, Rattan SI. Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. Exp Gerontol 2013; 48:94–98.

    CAS  PubMed  Google Scholar 

  59. Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 2001; 3:75–80.

    CAS  PubMed  Google Scholar 

  60. Deng ZB, Poliakov A, Hardy RW, Clements R, Liu C, Liu Y, et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes 2009; 58:2498–2505.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early alzheimer disease. J Biol Chem 2012; 287:3842–3849.

    CAS  PubMed  Google Scholar 

  62. Azevedo L, Janiszewski M, Pontieri V, Pedro A, Bassi E, Tucci P, Laurindo F. Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care 2007; 11:R120.

    PubMed  PubMed Central  Google Scholar 

  63. Tabernero J, Shapero GI, Larusso PM, Cervantes A, et al. First in man trial of an siRNA targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 2013; 14:5338–5366.

    Google Scholar 

  64. Zhang H, Liu C, Su K, Yu S, Zhang L, Zhang S, et al. A membrane form of TNF-α presented by exosomes delays T cell activation-induced cell death. J Immunol 2006; 176:7385–7393.

    CAS  PubMed  Google Scholar 

  65. Martinez-Lostao L, García-Alvarez F, Basáñez G, Alegre-Aguarón E, Desportes P, Larrad L, et al. Liposome-bound apo2l/trail is an effective treatment in a rabbit model of rheumatoid arthritis. Arthritis Rheum 2010; 62:2272–2282.

    CAS  PubMed  Google Scholar 

  66. Liang B, Peng P, Chen S, Li L, Zhang M, Cao D, et al. Characterization and proteomic analysis of ovarian cancer-derived exosomes. J Proteomics 2013; 80C:171–182.

    CAS  PubMed  Google Scholar 

  67. Takeshita N, Hoshino I, Mori M, Akutsu Y, Hanari N, Yoneyama Y, et al. Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. Br J Cancer 2013; 108:644–652.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kalra H, Simpson R, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: A compendium for extracellular vesicles with continuous community annotation. PLoS Biol 2012; 10:e1001450.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. El-Andaloussi S, Lee Y, Lakhal-Littleton S, Li J, Seow Y, Gardiner C, et al. Exosome-mediated delivery of sirna in vitro and in vivo. Nat Protoc 2012; 7:2112–2126.

    CAS  PubMed  Google Scholar 

  70. Anna G, John D, Jean F, LeAnna S, Toegel FE, Reiss GR et al. Initial report on a phase I clinical trial: prevention and treatment of post-operative acute kidney injury with allogeneic mesenchymal stem cells in patients who require on-pump cardiac surgery. Cell Ther Transplant 2008/01.

  71. Camussi G, Deregibus MC, Bruno S, et al. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 2010; 78:838–848.

    CAS  PubMed  Google Scholar 

  72. L Biancone, S Bruno, MC Deregibus, C Tetta, G Camussi. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 2012; 27:3037–3042.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wael Nassar MD.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nassar, W., El-Ansary, M., Aziz, M.A. et al. Extracellular vesicles: fundamentals and clinical relevance. Egypt J Intern Med 27, 1–7 (2015). https://doi.org/10.4103/1110-7782.155824

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.4103/1110-7782.155824

Keywords

  • exosomes
  • extracellular vesicles
  • horizontal gene transfer
  • microvesicles