Advertisement

Biologia

, Volume 73, Issue 4, pp 437–448 | Cite as

Extracellular vesicles – biogenesis, composition, function, uptake and therapeutic applications

  • Eva Petrovčíková
  • Kristína Vičíková
  • Vladimír Leksa
Review
  • 55 Downloads

Abstract

Extracellular vesicles are heterogenous, nano-sized, membrane-limited structures which not only represent a specific way of intercellular communication but also endow cells with many capabilities. Apoptotic bodies created during apoptosis, microvesicles shed from the plasma membrane, and exosomes originated inside the cell and released to extracellular space upon fusion with the plasma membrane, they all belong to extracellular vesicles. Extracellular vesicles contain lipids, proteins, and nucleic acids. In this review, we describe their biogenesis, release and uptake by recipient cells, their composition, functions and potential therapeutic and diagnostic applications.

Keywords

Extracellular vesicles Uptake Therapeutic application Multi-vesicular bodies 

Abbreviations

EVs

Extracellular vesicles

MVs

Microvesicles

MVBs

Multi-vesicular bodies

ILVs

Intraluminal vesicles

ARF6

ADP-ribosylation factor 6

PLD

Phospholipase D

ERK

Extracellular signal-regulated kinase

MLCK

Myosin light chain kinase

MHC-I

Major histocompatibility complex class-I molecules

VAMP3

Vesicle-associated membrane protein 3

MT1-MMP

Membrane type-1 matrix metalloproteinase

ESCRT

Endosomal sorting complex required for transport

VPS4

Vacuolar protein sorting-associated protein 4

ALIX

ALG-2-interacting protein X

TSG101

Tumour susceptibility gene 101

ARRDC1

Arrestin 1 domain–containing protein 1

VPS4

Vacuolar protein sorting-associated protein 4

WWP2

E3 ligase WW domain-containing protein 2

TCRs

T cell receptors

LAMP-3

Lysosomal-associated membrane protein 3

nSMase

Neutral sphingomyelinase

MFGE8

Milk fat globule-EGF factor 8

TIM4

T cell immunoglobulin mucin 4

TSP

Thrombospondin

MMPs

Matrix metalloproteinases

ADAM10

A disintegrin and metalloprotease 10

TACE

Tumour necrosis factor α-converting enzyme

siRNA

Small interfering RNA

TGF-β

transforming growth factor beta

LFA-1

lymphocyte function-associated antigen 1

ICAM-1

Intercellular adhesion molecule 1

HSPs

Heat shock proteins

DC

Dendritic cell

STB

Syncytiotrophoblast

TLR4

Toll-like receptor 4

PI3K/Akt

Phosphatidylinositol-3-kinases/protein kinase B

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

Tspan8

Tetraspanin 8

MCL

Mantle cell lymphoma

DC-SIGN

Dendritic cell-specific ICAM-grabbing non-integrin

MUC1

Mucin 1

TIM1

T-cell immunoglobulin and mucin domain 1

BAI1

Brain-specific angiogenesis inhibitor 1

uPAR

Urokinase-type plasminogen activator receptor

EGFRvIII

Epidermal growth factor receptor variant III

RHEB

Ras homolog enriched in brain

IFN-γ

Interferon gamma

STAT

Signal transducer and activator of transcription

VSV-G

Vesicular stomatitis virus glycoprotein

Notes

Acknowledgments

The work was supported by the FWF (P22908), VEGA (2/0063/14 and 2/0020/17) and APVV-16-0452 grants.

References

  1. Admyre C, Grunewald J, Thyberg J, Gripenbäck S, Tornling G, Eklund A, Scheynius A, Gabrielsson S (2003) Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J 22:578–583.  https://doi.org/10.1183/09031936.03.00041703 PubMedCrossRefGoogle Scholar
  2. Admyre C, Johansson SM, Qazi KR, Filén JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179:1969–1978.  https://doi.org/10.4049/jimmunol.179.3.1969 PubMedCrossRefGoogle Scholar
  3. Akers JC, Gonda D, Kim R, Carter BS, Chen CC (2013) Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neuro-Oncol 113:1–11.  https://doi.org/10.1007/s11060-013-1084-8 CrossRefGoogle Scholar
  4. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624.  https://doi.org/10.1038/ncb1725 PubMedCrossRefGoogle Scholar
  5. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345.  https://doi.org/10.1038/nbt.1807 PubMedCrossRefGoogle Scholar
  6. Andre F, Schartz NEC, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360:295–305.  https://doi.org/10.1016/S0140-6736(02)09552-1 PubMedCrossRefGoogle Scholar
  7. Aplin AE, Howe A, Alahari SK, Juliano RL (1998) Signal transduction and signal modulation by cell adhesion receptors: the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol Rev 50:197–263PubMedGoogle Scholar
  8. Atay S, Gercel-Taylor C, Taylor DD (2011) Human trophoblast-derived exosomal fibronectin induces pro-inflammatory IL-1β production by macrophages. Am J Reprod Immunol 66:259–269.  https://doi.org/10.1111/j.1600-0897.2011.00995.x PubMedCrossRefGoogle Scholar
  9. Bakhti M, Winter C, Simons M (2011) Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J Biol Chem 286:787–796.  https://doi.org/10.1074/jbc.M110.190009 PubMedCrossRefGoogle Scholar
  10. Barreca MM, Spinello W, Cavalieri V, Turturici G, Sconzo G, Kaur P, Tinnirello R, Asea AAA, Geraci F (2017) Extracellular Hsp70 Enhances Mesoangioblast Migration via an Autocrine Signaling Pathway. J Cell Physiol 232:1845–1861.  https://doi.org/10.1002/jcp.25722 PubMedCrossRefGoogle Scholar
  11. Barrés C, Blanc L, Bette-Bobillo P, André S, Mamoun R, Gabius HJ, Vidal M (2010) Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115:696–705.  https://doi.org/10.1182/blood-2009-07-231449 PubMedCrossRefGoogle Scholar
  12. Berckmans RJ, Sturk A, van Tienen LM, Schaap MC, Nieuwland R (2011) Cell-derived vesicles exposing coagulant tissue factor in saliva. Blood 117:3172–3180.  https://doi.org/10.1182/blood-2010-06-290460 PubMedCrossRefGoogle Scholar
  13. Berditchevski F, Odintsova E (2007) Tetraspanins as regulators of protein trafficking. Traffic 8:89-96.  https://doi.org/10.1111/j.1600-0854.2006.00515.x
  14. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C (2002) TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol 168:3235–3241.  https://doi.org/10.4049/jimmunol.168.7.3235 PubMedCrossRefGoogle Scholar
  15. Bobrie A, Théry C (2013) Exosomes and communication between tumours and the immune system: are all exosomes equal? Biochem Soc Trans 41:263–267.  https://doi.org/10.1042/BST20120245 PubMedCrossRefGoogle Scholar
  16. Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O'Donnell E, Farndale RW, Ware J, Lee DM (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327:580–583.  https://doi.org/10.1126/science.1181928 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Busch A, Quast T, Keller S, Kolanus W, Knolle P, Altevogt P, Limmer A (2008) Transfer of T cell surface molecules to dendritic cells upon CD4+ T cell priming involves two distinct mechanisms. J Immunol 181:3965–3973.  https://doi.org/10.4049/jimmunol.181.6.3965 PubMedCrossRefGoogle Scholar
  18. Buschow SI, Nolte-‘t Hoen EN, van Niel G, Pols MS, ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH, Stoorvogel W (2009) MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10:1528–1542.  https://doi.org/10.1111/j.1600-0854.2009.00963.x PubMedCrossRefGoogle Scholar
  19. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17:879–887.  https://doi.org/10.1093/intimm/dxh267 PubMedCrossRefGoogle Scholar
  20. Candela ME, Geraci F, Turturici G, Taverna S, Albanese I, Sconzo G (2010) Membrane vesicles containing matrix metalloproteinase-9 and fibroblast growth factor-2 are released into the extracellular space from mouse mesoangioblast stem cells. J Cell Physiol 224:144–151.  https://doi.org/10.1002/jcp.22111 PubMedCrossRefGoogle Scholar
  21. Carayon K, Chaoui K, Ronzier E, Lazar I, Bertrand-Michel J, Roques V, Balor S, Terce F, Lopez A, Salomé L, Joly E (2011) The proteolipidic composition of exosomes changes during reticulocyte maturation. J Biol Chem 286:34426–34439.  https://doi.org/10.1074/jbc.M111.257444 PubMedPubMedCentralCrossRefGoogle Scholar
  22. Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res 38:215–224.  https://doi.org/10.1093/nar/gkp857 PubMedCrossRefGoogle Scholar
  23. Choudhuri K, Llodrá J, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL, Dustin ML (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118–123.  https://doi.org/10.1038/nature12951 PubMedPubMedCentralCrossRefGoogle Scholar
  24. Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A 110:17380–17385.  https://doi.org/10.1073/pnas.1304266110 PubMedPubMedCentralCrossRefGoogle Scholar
  25. Clayton A, Harris CL, Court J, Mason MD, Morgan BP (2003) Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur J Immunol 33:522–531.  https://doi.org/10.1002/immu.200310028 PubMedCrossRefGoogle Scholar
  26. Colombo M, Raposo G, Théry C (2014) Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. Annu Rev Cell Dev Biol 30:255–289.  https://doi.org/10.1146/annurev-cellbio-101512-122326 PubMedCrossRefGoogle Scholar
  27. Cossetti C, Iraci N, Mercer TR, Leonardi T, Alpi E, Drago D, Alfaro-Cervello C, Saini HK, Davis MP, Schaeffer J, Vega B, Stefanini M, Zhao C, Muller W, Garcia-Verdugo JM, Mathivanan S, Bachi A, Enright AJ, Mattick JS, Pluchino S (2014) Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signaling in target cells. Mol Cell 56:193–204.  https://doi.org/10.1016/j.molcel.2014.08.020 PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dai S, Wan T, Wang B, Zhou X, Xiu F, Chen T, Wu Y, Cao X (2005) More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 11:7554–7563.  https://doi.org/10.1158/1078-0432.CCR-05-0810 PubMedCrossRefGoogle Scholar
  29. DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM (2010) T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol 184:1918–1930.  https://doi.org/10.4049/jimmunol.0903059 PubMedPubMedCentralCrossRefGoogle Scholar
  30. Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, Geuze HJ (2000) Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol 165:1259–1265.  https://doi.org/10.4049/jimmunol.165.3.1259 PubMedCrossRefGoogle Scholar
  31. D'Mello V, Singh S, Wu Y, Birge RB (2009) The urokinase plasminogen activator receptor promotes efferocytosis of apoptotic cells. J Biol Chem 284:17030–17038.  https://doi.org/10.1074/jbc.M109.010066 PubMedPubMedCentralCrossRefGoogle Scholar
  32. Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, Carvalho AC (1981) Tumor shedding and coagulation. Science 212:923–924.  https://doi.org/10.1126/science.7195067 PubMedCrossRefGoogle Scholar
  33. Edgar JR, Eden ER, Futter CE (2014) Hrs- and CD63-dependent competing mechanisms make different sized endosomal intraluminal vesicles. Traffic 15:197–211.  https://doi.org/10.1111/tra.12139 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Escrevente C, Keller S, Altevogt P, Costa J (2011) Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer 11:108.  https://doi.org/10.1186/1471-2407-11-108 PubMedPubMedCentralCrossRefGoogle Scholar
  35. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116.  https://doi.org/10.1073/pnas.1209414109 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Fauré J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, Kirchhoff F, Raposo G, Garin J, Sadoul R (2006) Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31:642–648.  https://doi.org/10.1016/j.mcn.2005.12.003 PubMedCrossRefGoogle Scholar
  37. Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF, Zhou Q, Sui SF (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11:675–687.  https://doi.org/10.1111/j.1600-0854.2010.01041.x PubMedCrossRefGoogle Scholar
  38. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101:9683–9688.  https://doi.org/10.1073/pnas.0308413101 PubMedPubMedCentralCrossRefGoogle Scholar
  39. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124:447–458.  https://doi.org/10.1242/jcs.074088 PubMedCrossRefGoogle Scholar
  40. Friggeri A, Yang Y, Banerjee S, Park YJ, Liu G, Abraham E (2010) HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin. Am J Phys Cell Physiol 299:C1267–C1276.  https://doi.org/10.1152/ajpcell.00152.2010 CrossRefGoogle Scholar
  41. Frühbeis C, Fröhlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Möbius W, Goebbels S, Nave KA, Schneider A, Simons M, Klugmann M, Trotter J, Krämer-Albers EM (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11:e1001604.  https://doi.org/10.1371/journal.pbio.1001604 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Garcia-Vallejo JJ, van Kooyk Y (2013) The physiological role of DC-SIGN: a tale of mice and men. Trends Immunol 34:482–486.  https://doi.org/10.1016/j.it.2013.03.001 PubMedCrossRefGoogle Scholar
  43. Gasser O, Schifferli JA (2004) Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 104:2543–2548.  https://doi.org/10.1182/blood-2004-01-0361 PubMedCrossRefGoogle Scholar
  44. Ghossoub R, Lembo F, Rubio A, Gaillard CB, Bouchet J, Vitale N, Slavík J, Machala M, Zimmermann P (2014) Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun 5:3477.  https://doi.org/10.1038/ncomms4477 PubMedCrossRefGoogle Scholar
  45. Goligorsky MS, Addabbo F, O’Riordan E (2007) Diagnostic potential of urine proteome: a broken mirror of renal diseases. J Am Soc Nephrol 18:2233–2239.  https://doi.org/10.1681/ASN.2006121399 PubMedCrossRefGoogle Scholar
  46. Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R, Hazen SL (2006) Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med 203:2613–2625.  https://doi.org/10.1084/jem.20060370 PubMedPubMedCentralCrossRefGoogle Scholar
  47. Gregory CD, Devitt A, Moffatt O (1998) Roles of ICAM-3 and CD14 in the recognition and phagocytosis of apoptotic cells by macrophages. Biochem Soc Trans 26:644–649.  https://doi.org/10.1042/bst0260644 PubMedCrossRefGoogle Scholar
  48. Hakulinen J, Sankkila L, Sugiyama N, Lehti K, Keski-Oja J (2008) Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J Cell Biochem 105:1211–1218.  https://doi.org/10.1002/jcb.21923 PubMedCrossRefGoogle Scholar
  49. Han KY, Dugas-Ford J, Seiki M, Chang JH, Azar DT (2015) Evidence for the involvement of MMP14 in MMP2 processing and recruitment in exosomes of corneal fibroblasts. Invest Ophthalmol Vis Sci 56:5323–5329.  https://doi.org/10.1167/iovs.14-14417 PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187.  https://doi.org/10.1038/417182a PubMedCrossRefGoogle Scholar
  51. Hanson PI, Cashikar A (2012) Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 28:337–362.  https://doi.org/10.1146/annurev-cellbio-092910-154152 PubMedCrossRefGoogle Scholar
  52. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–339.  https://doi.org/10.1083/jcb.97.2.329 PubMedCrossRefGoogle Scholar
  53. Hazan-Halevy I, Rosenblum D, Weinstein S, Bairey O, Raanani P, Peer D (2015) Cell-specific uptake of mantle cell lymphoma-derived exosomes by malignant and non-malignant B-lymphocytes. Cancer Lett 364:59–69.  https://doi.org/10.1016/j.canlet.2015.04.026 PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva-Nilsson L (2011) Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One 6:e16899.  https://doi.org/10.1371/journal.pone.0016899 PubMedPubMedCentralCrossRefGoogle Scholar
  55. Heijnen HFG, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3800PubMedGoogle Scholar
  56. Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811.  https://doi.org/10.1038/nrm1736 PubMedCrossRefGoogle Scholar
  57. Hiemstra TF, Charles PD, Gracia T, Hester SS, Gatto L, Al-Lamki R, Floto RA, Su Y, Skepper JN, Lilley KS, Karet Frankl FE (2014) Human urinary exosomes as innate immune effectors. J Am Soc Nephrol 25:2017–2027.  https://doi.org/10.1681/ASN.2013101066 PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71:3792–3801.  https://doi.org/10.1158/0008-5472.CAN-10-4455 PubMedCrossRefGoogle Scholar
  59. Hosseini A, Soleimani S, Pezeshgi Modarres H, Hojjati Emami S, Tondar M, Bahlakeh G, Hasani-Sadrabad MM (2016) Exosome-inspired targeting of cancer cells with enhanced affinity. J Mater Chem B 4:768–778.  https://doi.org/10.1039/C5TB01741F CrossRefGoogle Scholar
  60. Hulín I (2009) Hulínová patofyziológia: exkrečné funkcie obličiek a ich poruchy. In: Hulín I (ed) Hulínova patofyziológia, 7th edn. Slovak Academic Press, Bratislava, pp 782–788Google Scholar
  61. Izquierdo-Useros N, Naranjo-Gómez M, Archer J, Hatch SC, Erkizia I, Blanco J, Borràs FE, Puertas MC, Connor JH, Fernández-Figueras MT, Moore L, Clotet B, Gummuluru S, Martinez-Picado J (2009) Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 113:2732–2741.  https://doi.org/10.1182/blood-2008-05-158642 PubMedPubMedCentralCrossRefGoogle Scholar
  62. Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760.  https://doi.org/10.1002/ijc.20657 PubMedCrossRefGoogle Scholar
  63. Jung T, Castellana D, Klingbeil P, Cuesta Hernández I, Vitacolonna M, Orlicky DJ, Roffler SR, Brodt P, Zöller M (2009) CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11:1093–1105.  https://doi.org/10.1593/neo.09822 PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, Bond VC, Borràs FE, Breakefield X, Budnik V, Buzas E, Camussi G, Clayton A, Cocucci E, Falcon-Perez JM, Gabrielsson S, Gho YS, Gupta D, Harsha HC, Hendrix A, Hill AF, Inal JM, Jenster G, Krämer-Albers EM, Lim SK, Llorente A, Lötvall J, Marcilla A, Mincheva-Nilsson L, Nazarenko I, Nieuwland R, Nolte'-t Hoen EN, Pandey A, Patel T, Piper MG, Pluchino S, Prasad TS, Rajendran L, Raposo G, Record M, Reid GE, Sánchez-Madrid F, Schiffelers RM, Siljander P, Stensballe A, Stoorvogel W, Taylor D, Thery C, Valadi H, van Balkom BW, Vázquez J, Vidal M, Wauben MH, Yáñez-Mó M, Zoeller M, Mathivanan S (2012) Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 10:e1001450.  https://doi.org/10.1371/journal.pbio.1001450 PubMedPubMedCentralCrossRefGoogle Scholar
  65. Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, Hager HD, Abdel-Bakky MS, Gutwein P, Altevogt P (2007) CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int 72:1095–1102.  https://doi.org/10.1038/sj.ki.5002486 PubMedCrossRefGoogle Scholar
  66. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257.  https://doi.org/10.1038/bjc.1972.33 PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kleinjan A, Böing AN, Sturk A, Nieuwland R (2012) Microparticles in vascular disorders: how tissue factor-exposing vesicles contribute to pathology and physiology. Thromb Res 130:S71–S73.  https://doi.org/10.1016/j.thromres.2012.08.281 PubMedCrossRefGoogle Scholar
  68. Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F, Adhikary D, Mautner J, Busson P (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood 113:1957–1966.  https://doi.org/10.1182/blood-2008-02-142596 PubMedCrossRefGoogle Scholar
  69. Kobayashi N, Karisola P, Pena-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927–940.  https://doi.org/10.1016/j.immuni.2007.11.011 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Kooijmans SAA, Fliervoet LAL, van der Meel R, Fens MHAM, Heijnen HFG, van Bergen En Henegouwen PMP, Vader P, Schiffelers RM (2016) PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release 224:77–85.  https://doi.org/10.1016/j.jconrel.2016.01.009 PubMedCrossRefGoogle Scholar
  71. Krämer-Albers EM, Bretz N, Tenzer S, Winterstein C, Möbius W, Berger H, Nave KA, Schild H, Trotter J (2007) Oligodendrocytes secrete exosomes containing major myelin and stress- protective proteins: trophic support for axons? Proteomics Clin Appl 1:1446–1461.  https://doi.org/10.1002/prca.200700522 PubMedCrossRefGoogle Scholar
  72. Lachenal G, Pernet-Gallay K, Chivet M, Hemming FJ, Belly A, Bodon G, Blot B, Haase G, Goldberg Y, Sadoul R (2011) Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci 46:409–418.  https://doi.org/10.1016/j.mcn.2010.11.004 PubMedCrossRefGoogle Scholar
  73. Lakkaraju A, Rodriguez-Boulan E (2008) Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 18:199–209.  https://doi.org/10.1016/j.tcb.2008.03.002 PubMedPubMedCentralCrossRefGoogle Scholar
  74. Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux JF, Kobayashi T, Salles JP, Perret B, Bonnerot C, Record M (2004) Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J 380:161–171.  https://doi.org/10.1042/bj20031594 PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lee SJ, So IS, Park SY, Kim IS (2008) Thymosin beta4 is involved in stabilin-2-mediated apoptotic cell engulfment. FEBS Lett 582:2161–2166.  https://doi.org/10.1016/j.febslet.2008.03.058 PubMedCrossRefGoogle Scholar
  76. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733.  https://doi.org/10.1038/cdd.2008.104 PubMedCrossRefGoogle Scholar
  77. Lu J, Li J, Liu S, Wang T, Ianni A, Bober E, Braun T, Xiang R, Yue S (2017) Exosomal tetraspanins mediate cancer metastasis by altering host microenvironment. Oncotarget 8:62803–62815.  https://doi.org/10.18632/oncotarget.19119 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, Paris L, Abalsamo L, Colone M, Molinari A, Podo F, Rivoltini L, Ramoni C, Fais S (2012) Immune surveillance properties of human NK cell-derived exosomes. J Immunol 189:2833–2842.  https://doi.org/10.4049/jimmunol.1101988 PubMedCrossRefGoogle Scholar
  79. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, Lin HM, Shang CZ, Chen YJ, Min J (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287:15874–15885.  https://doi.org/10.1074/jbc.M112.340588 PubMedPubMedCentralCrossRefGoogle Scholar
  80. Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, Heath JK, Raposo G, Cerf-Bensussan N, Heyman M (2007) T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 132:1866–1876.  https://doi.org/10.1053/j.gastro.2007.02.043 PubMedCrossRefGoogle Scholar
  81. Marton A, Vizler C, Kusz E, Temesfoi V, Szathmary Z, Nagy K, Szegletes Z, Varo G, Siklos L, Katona RL, Tubak V, Howard OM, Duda E, Minarovits J, Nagy K, Buzas K (2012) Melanoma cell-derived exosomes alter macrophage and dendritic cell functions in vitro. Immunol Lett 148:34–38.  https://doi.org/10.1016/j.imlet.2012.07.006 PubMedCrossRefGoogle Scholar
  82. Mastronardi ML, Mostefai HA, Meziani F, Martinez MC, Asfar P, Andriantsitohaina R (2011) Circulating microparticles from septic shock patients exert differential tissue expression of enzymes related to inflammation and oxidative stress. Crit Care Med 39:1739–1748.  https://doi.org/10.1097/CCM.0b013e3182190b4b PubMedCrossRefGoogle Scholar
  83. Masyuk AI, Huang BQ, Ward CJ, Gradilone SA, Banales JM, Masyuk TV, Radtke B, Splinter PL, LaRusso NF (2010) Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol 299:G990–G999.  https://doi.org/10.1152/ajpgi.00093.2010 PubMedPubMedCentralCrossRefGoogle Scholar
  84. Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteome 73:1907–1920.  https://doi.org/10.1016/j.jprot.2010.06.006 CrossRefGoogle Scholar
  85. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ, Bernad A, Sánchez-Madrid F (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282.  https://doi.org/10.1038/ncomms1285 PubMedPubMedCentralCrossRefGoogle Scholar
  86. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439.  https://doi.org/10.1038/nature06307 PubMedCrossRefGoogle Scholar
  87. Möbius W, Ohno-Iwashita Y, van Donselaar EG, Oorschot VM, Shimada Y, Fujimoto T, Heijnen HF, Geuze HJ, Slot JW (2002) Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J Histochem Cytochem 50:43–55.  https://doi.org/10.1177/002215540205000105 PubMedCrossRefGoogle Scholar
  88. Monleón I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taulés M, Iturralde M, Piñeiro A, Larrad L, Alava MA, Naval J, Anel A (2001) 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.  https://doi.org/10.4049/jimmunol.167.12.6736 PubMedCrossRefGoogle Scholar
  89. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, Milosevic J, Tkacheva OA, Divito SJ, Jordan R, Lyons-Weiler J, Watkins SC, Morelli AE (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766.  https://doi.org/10.1182/blood-2011-02-338004 PubMedPubMedCentralCrossRefGoogle Scholar
  90. Morelli AE (2006) The immune regulatory effect of apoptotic cells and exosomes on dendritic cells: its impact on transplantation. Am J Transplant 6:254–261.  https://doi.org/10.1111/j.1600-6143.2005.01197.x PubMedCrossRefGoogle Scholar
  91. Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD Jr, Thomson AW (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–3266.  https://doi.org/10.1182/blood-2004-03-0824 PubMedCrossRefGoogle Scholar
  92. Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3.  https://doi.org/10.3402/jev.v3.24641
  93. Muralidharan-Chari V, Clancy J, Plou C, Romao M, Chavrier P, Raposo G, D'Souza-Schorey C (2009) ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr Biol 19:1875–1885.  https://doi.org/10.1016/j.cub.2009.09.059 PubMedPubMedCentralCrossRefGoogle Scholar
  94. Nabhan JF, Hu R, Oh RS, Cohen SN, Lu Q (2012) Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc Natl Acad Sci U S A 109:4146–4151.  https://doi.org/10.1073/pnas.1200448109 PubMedPubMedCentralCrossRefGoogle Scholar
  95. Nanbo A, Kawanishi E, Yoshida R, Yoshiyama H (2013) Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol 87:10334–10347.  https://doi.org/10.1128/JVI.01310-13 PubMedPubMedCentralCrossRefGoogle Scholar
  96. Näslund TI, Paquin-Proulx D, Paredes PT, Vallhov H, Sandberg JK, Gabrielsson S (2014) Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells. AIDS 28:171–180.  https://doi.org/10.1097/QAD.0000000000000159 PubMedCrossRefGoogle Scholar
  97. Nguyen DG, Booth A, Gould SJ, Hildreth JE (2003) Evidence that HIV budding in primary macrophages occurs through the exosome release pathway. J Biol Chem 278:52347–52354.  https://doi.org/10.1074/jbc.M309009200 PubMedCrossRefGoogle Scholar
  98. Nolte-'t Hoen EN, Wauben MH (2012) Immune cell-derived vesicles: modulators and mediators of inflammation. Curr Pharm Des 18:2357–2368.  https://doi.org/10.2174/138161212800166013 PubMedCrossRefGoogle Scholar
  99. Nolte-'t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W, Wauben MH (2009) Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977–1981.  https://doi.org/10.1182/blood-2008-08-174094 PubMedCrossRefGoogle Scholar
  100. Ogawa Y, Kanai-Azuma M, Akimoto Y, Kawakami H, Yanoshita R (2008) Exosome-like vesicles with dipeptidyl peptidase IV in human saliva. Biol Pharm Bull 31:1059–1062.  https://doi.org/10.1248/bpb.31.1059 PubMedCrossRefGoogle Scholar
  101. Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–978.  https://doi.org/10.1016/0092-8674(83)90040-5 PubMedCrossRefGoogle Scholar
  102. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:430–434.  https://doi.org/10.1038/nature06329 PubMedCrossRefGoogle Scholar
  103. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222.  https://doi.org/10.1074/jbc.M109.041152 PubMedPubMedCentralCrossRefGoogle Scholar
  104. Patel B, Patel J, Cho JH, Manne S, Bonala S, Henske E, Roegiers F, Markiewski M, Karbowniczek M (2015) Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex. Oncogene 35:3027–3036.  https://doi.org/10.1038/onc.2015.358 PubMedCrossRefGoogle Scholar
  105. Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101:13368–13373.  https://doi.org/10.1073/pnas.0403453101 PubMedPubMedCentralCrossRefGoogle Scholar
  106. Poliakov A, Spilman M, Dokland T, Amling CL, Mobley JA (2009) Structural heterogeneity and protein composition of exosome-like vesicles (prostasomes) in human semen. Prostate 69:159–167.  https://doi.org/10.1002/pros.20860 PubMedCrossRefGoogle Scholar
  107. Qu JL, Qu XJ, Zhao MF, Teng YE, Zhang Y, Hou KZ, Jiang YH, Yang XH, Liu YP (2009a) Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation. Dig Liver Dis 41:875–880.  https://doi.org/10.1016/j.dld.2009.04.006 PubMedCrossRefGoogle Scholar
  108. Qu Y, Ramachandra L, Mohr S, Franchi L, Harding CV, Nunez G, Dubyak GR (2009b) P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J Immunol 182:5052–5062.  https://doi.org/10.4049/jimmunol.0802968 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A 103:11172–11177.  https://doi.org/10.1073/pnas.0603838103 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Rak J (2010) Microparticles in cancer. Semin Thromb Hemost 36:888–906.  https://doi.org/10.1055/s-0030-1267043 PubMedCrossRefGoogle Scholar
  111. Ramachandra L, Qu Y, Wang Y, Lewis CJ, Cobb BA, Takatsu K, Boom WH, Dubyak GR, Harding CV (2010) Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing major histocompatibility complex class II molecules capable of antigen presentation. Infect Immun 78:5116–5125.  https://doi.org/10.1128/IAI.01089-09 PubMedPubMedCentralCrossRefGoogle Scholar
  112. Rana S, Zöller M (2011) Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis. Biochem Soc Trans 39:559–562.  https://doi.org/10.1042/BST0390559 PubMedCrossRefGoogle Scholar
  113. Rana S, Yue S, Stadel D, Zöller M (2012) Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 44:1574–1584.  https://doi.org/10.1016/j.biocel.2012.06.018 PubMedCrossRefGoogle Scholar
  114. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles and friends. J Cell Biol 200:373–383.  https://doi.org/10.1083/jcb.201211138 PubMedPubMedCentralCrossRefGoogle Scholar
  115. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172.  https://doi.org/10.1084/jem.183.3.1161 PubMedCrossRefGoogle Scholar
  116. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20:1487–1495.  https://doi.org/10.1038/sj.leu.2404296 PubMedCrossRefGoogle Scholar
  117. Record M, Carayon K, Poirot M, Silvente-Poirot S (2014) Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta 1841:108–120.  https://doi.org/10.1016/j.bbalip.2013.10.004 PubMedCrossRefGoogle Scholar
  118. Rhee JS, Black M, Schubert U, Fischer S, Morgenstern E, Hammes HP, Preissner KT (2004) The functional role of blood platelet components in angiogenesis. Thromb Haemost 92:394–402.  https://doi.org/10.1160/TH03-04-0213 PubMedCrossRefGoogle Scholar
  119. Roucourt B, Meeussen S, Bao J, Zimmermann P, David G (2015) Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res 25:412–428.  https://doi.org/10.1038/cr.2015.29 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Sadovska L, Santos CB, Kalniņa Z, Linē A (2015) Biodistribution, Uptake and Effects Caused by Cancer-derived Extracellular Vesicles. J Circ Biomark 4:2.  https://doi.org/10.5772/60522 PubMedPubMedCentralCrossRefGoogle Scholar
  121. Saunderson SC, Dunn AC, Crocker PR, McLellan AD (2014) CD169 mediates the capture of exosomes in spleen and lymph node. Blood 123:208–216.  https://doi.org/10.1182/blood-2013-03-489732 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Schnitzer JK, Berzel S, Fajardo-Moser M, Remer KA, Moll H (2010) Fragments of antigen-loaded dendritic cells (DC) and DC-derived exosomes induce protective immunity against Leishmania major. Vaccine 28:5785–5793.  https://doi.org/10.1016/j.vaccine.2010.06.077 PubMedCrossRefGoogle Scholar
  123. Segura E, Guérin C, Hogg N, Amigorena S, Théry C (2007) CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J Immunol 179:1489–1496.  https://doi.org/10.4049/jimmunol.179.3.1489 PubMedCrossRefGoogle Scholar
  124. Simons M, Raposo G (2009) Exosomes – vesicular carriers for intracellular communication. Curr Opin Cell Biol 21:575–581.  https://doi.org/10.1016/j.ceb.2009.03.007 PubMedCrossRefGoogle Scholar
  125. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476.  https://doi.org/10.1038/ncb1800 PubMedPubMedCentralCrossRefGoogle Scholar
  126. Skokos D, LePanse S, Villa I, Rousselle JC, Peronet R, David B, Namane A, Mécheri S (2001) Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol 166:868–876.  https://doi.org/10.4049/jimmunol.166.2.868 PubMedCrossRefGoogle Scholar
  127. Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, Boudaly S, Mécheri S (2003) Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol 170:3037–3045.  https://doi.org/10.4049/jimmunol.170.6.3037 PubMedCrossRefGoogle Scholar
  128. Skriner K, Adolph K, Jungblut PR, Burmester GR (2006) Association of citrullinated proteins with synovial exosomes. Arthritis Rheum 54:3809–3814.  https://doi.org/10.1002/art.22276 PubMedCrossRefGoogle Scholar
  129. Smyth TJ, Redzic JS, Graner MW, Anchordoquy TJ (2014) Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro. Biochim Biophys Acta 1838:2954–2965.  https://doi.org/10.1016/j.bbamem.2014.07.026 PubMedPubMedCentralCrossRefGoogle Scholar
  130. Stepanek O, Brdicka T, Angelisova P, Horvath O, Spicka J, Stockbauer P, Man P, Horejsi V (2011) Interaction of late apoptotic and necrotic cells with vitronectin. PLoS One 6:e19243.  https://doi.org/10.1371/journal.pone.0019243 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Stoeck A, Keller S, Riedle S, Sanderson MP, Runz S, Le Naour F, Gutwein P, Ludwig A, Rubinstein E, Altevogt P (2006) A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem J 393:609–618.  https://doi.org/10.1042/BJ20051013 PubMedPubMedCentralCrossRefGoogle Scholar
  132. Svensson KJ, Christianson HC, Wittrup A, Bourseau-Guilmain E, Lindqvist E, Svensson LM, Mörgelin M, Belting M (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288:17713–17724.  https://doi.org/10.1074/jbc.M112.445403 PubMedPubMedCentralCrossRefGoogle Scholar
  133. Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, Lv M, Li D, Katirai F, Shen GX, Zhang G, Feng ZH, Ye D, Huan B (2012) Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat Commun 3:1282.  https://doi.org/10.1038/ncomms2282 PubMedCrossRefGoogle Scholar
  134. Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ (2012) Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods 56:293–304.  https://doi.org/10.1016/j.ymeth.2012.01.002 PubMedCrossRefGoogle Scholar
  135. Temchura VV, Tenbusch M, Nchinda G, Nabi G, Tippler B, Zelenyuk M, Wildner O, Uberla K, Kuate S (2008) Enhancement of immunostimulatory properties of exosomal vaccines by incorporation of fusion-competent G protein of vesicular stomatitis virus. Vaccine 26:3662–3672.  https://doi.org/10.1016/j.vaccine.2008.04.069 PubMedCrossRefGoogle Scholar
  136. Thali M (2009) The roles of tetraspanins in HIV-1 replication. Curr Top Microbiol Immunol 339:85–102.  https://doi.org/10.1007/978-3-642-02175-6_5 PubMedPubMedCentralCrossRefGoogle Scholar
  137. Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610.  https://doi.org/10.1083/jcb.147.3.599 PubMedPubMedCentralCrossRefGoogle Scholar
  138. Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579.  https://doi.org/10.1038/nri855 PubMedCrossRefGoogle Scholar
  139. Tian T, Wang Y, Wang H, Zhu Z, Xiao Z (2010) Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem 111:488–496.  https://doi.org/10.1002/jcb.22733 PubMedCrossRefGoogle Scholar
  140. Timár CI, Lörincz AM, Ligeti E (2013) Changing world of neutrophils. Pflugers Arch 465:1521–1533.  https://doi.org/10.1007/s00424-013-1285-1 PubMedCrossRefGoogle Scholar
  141. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247.  https://doi.org/10.1126/science.1153124 PubMedCrossRefGoogle Scholar
  142. Turturici G, Tinnirello R, Sconzo G, Geraci F (2014) Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am J Phys Cell Physiol 306:C621–C633.  https://doi.org/10.1152/ajpcell.00228.2013 CrossRefGoogle Scholar
  143. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659.  https://doi.org/10.1038/ncb1596 PubMedCrossRefGoogle Scholar
  144. van Eijk IC, Tushuizen ME, Sturk A, Dijkmans BA, Boers M, Voskuyl AE, Diamant M, Wolbink GJ, Nieuwland R, Nurmohamed MT (2010) Circulating microparticles remain associated with complement activation despite intensive anti-inflammatory therapy in early rheumatoid arthritis. Ann Rheum Dis 69:1378–1382.  https://doi.org/10.1136/ard.2009.118372 PubMedCrossRefGoogle Scholar
  145. Vella LJ, Greenwood DLV, Cappai R, Scheerlinck JPY, Hill AF (2008) Enrichment of prion protein in exosomes derived from bovine cerebral spinal fluid. Vet Immunol Immunopathol 124:385–393.  https://doi.org/10.1016/j.vetimm.2008.04.002 PubMedCrossRefGoogle Scholar
  146. Véron P, Segura E, Sugano G, Amigorena S, Théry C (2005) Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells. Blood Cells Mol Dis 35:81–88.  https://doi.org/10.1016/j.bcmd.2005.05.001 PubMedCrossRefGoogle Scholar
  147. Wang JG, Williams JC, Davis BK, Jacobson K, Doerschuk CM, Ting JPY, Mackman N (2011a) Monocytic microparticles activate endothelial cells in an IL-1β-dependent manner. Blood 118:2366–2374.  https://doi.org/10.1182/blood-2011-01-330878 PubMedPubMedCentralCrossRefGoogle Scholar
  148. Wang S, Cesca F, Loers G, Schweizer M, Buck F, Benfenati F, Schachner M, Kleene R (2011b) Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci 31:7275–7290.  https://doi.org/10.1523/JNEUROSCI.6476-10.2011 PubMedCrossRefGoogle Scholar
  149. Wang J, Wu Y, Guo J, Fei X, Yu L, Ma S (2017) Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells. Oncotarget 8:81880–81891.  https://doi.org/10.18632/oncotarget.18737 PubMedPubMedCentralCrossRefGoogle Scholar
  150. Wood MJ, O’Loughlin AJ, Samira L (2011) Exosomes and the blood-brain barrier: implications for neurological diseases. Ther Deliv 2:1095–1099.  https://doi.org/10.4155/TDE.11.83 PubMedCrossRefGoogle Scholar
  151. Wu Y, Singh S, Georgescu MM, Birge RB (2005) A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci 118:539–553.  https://doi.org/10.1242/jcs.01632 PubMedCrossRefGoogle Scholar
  152. Wu G, Yang G, Zhang R, Xu G, Zhang L, Wen W, Lu J, Liu J, Yu Y (2015) Altered microRNA expression profiles of extracellular vesicles in nasal mucus from patients with allergic rhinitis. Allergy, Asthma Immunol Res 7:449–457.  https://doi.org/10.4168/aair.2015.7.5.449 CrossRefGoogle Scholar
  153. Xitong D, Xiaorong Z (2016) Targeted therapeutic delivery using engineered exosomes and its applications in cardiovascular diseases. Gene 575:377–384.  https://doi.org/10.1016/j.gene.2015.08.067 PubMedCrossRefGoogle Scholar
  154. Yáñez-Mó M, Siljander PR, Andreu Z, Zavec AB, Borràs FE, Buzas EI, Buzas K, Casal E, Cappello F, Carvalho J, Colás E, Cordeiro-da Silva A, Fais S, Falcon-Perez JM, Ghobrial IM, Giebel B, Gimona M, Graner M, Gursel I, Gursel M, Heegaard NH, Hendrix A, Kierulf P, Kokubun K, Kosanovic M, Kralj-Iglic V, Krämer-Albers EM, Laitinen S, Lässer C, Lener T, Ligeti E, Linē A, Lipps G, Llorente A, Lötvall J, Manček-Keber M, Marcilla A, Mittelbrunn M, Nazarenko I, Nolte-'t Hoen EN, Nyman TA, O'Driscoll L, Olivan M, Oliveira C, Pállinger É, Del Portillo HA, Reventós J, Rigau M, Rohde E, Sammar M, Sánchez-Madrid F, Santarém N, Schallmoser K, Ostenfeld MS Stoorvogel W, Stukelj R, Van der Grein SG, Vasconcelos MH, Wauben MH, De Wever O (2015) Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 4:27066.  https://doi.org/10.3402/jev.v4.27066 PubMedCrossRefGoogle Scholar
  155. Yin W, Ghebrehiwet B, Peerschke EIB (2008) Expression of complement components and inhibitors on platelet microparticles. Platelets 19:225–233.  https://doi.org/10.1080/09537100701777311 PubMedPubMedCentralCrossRefGoogle Scholar
  156. Yoshioka Y, Konishi Y, Kosaka N, Katsuda T, Kato T, Ochiya T (2013) Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles 2.  https://doi.org/10.3402/jev.v2i0.20424
  157. You Y, Shan Y, Chen J, Yue H, You B, Shi S, Li X, Cao X (2015) Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis. Cancer Sci 106:1669–1677.  https://doi.org/10.1111/cas.12818 PubMedPubMedCentralCrossRefGoogle Scholar
  158. Zaborowski MP, Balaj L, Breakefield XO, Lai CP (2015) Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study. Bioscience 65:783–797.  https://doi.org/10.1093/biosci/biv084 PubMedPubMedCentralCrossRefGoogle Scholar
  159. Zech D, Rana S, Büchler MW, Zöller M (2012) Tumor-exosomes and leukocyte activation: an ambivalent crosstalk. Cell Commun Signal 10:37.  https://doi.org/10.1186/1478-811X-10-37 PubMedPubMedCentralCrossRefGoogle Scholar
  160. Zhou H, Pisitkun T, Aponte A, Yuen PS, Hoffert JD, Yasuda H, Hu X, Chawla L, Shen RF, Knepper MA, Star RA (2006) Exosomal fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. Kidney Int 70:1847–1857.  https://doi.org/10.1038/sj.ki.5001874 PubMedPubMedCentralCrossRefGoogle Scholar
  161. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600.  https://doi.org/10.1038/nm0598-594 PubMedCrossRefGoogle Scholar

Copyright information

© Institute of Molecular Biology, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Biochemistry DepartmentComenius UniversityBratislavaSlovakia
  2. 2.Laboratory of Molecular Immunology, Slovak Academy of SciencesInstitute of Molecular BiologyBratislavaSlovakia
  3. 3.Molecular Immunology Unit, Institute for Hygiene and Applies Immunology, Center for Pathophysiology, Infectology and ImmunologyMedical University of ViennaViennaAustria

Personalised recommendations