Korean J Physiol Pharmacol.  2018 Mar;22(2):113-125. 10.4196/kjpp.2018.22.2.113.

The potential theragnostic (diagnostic+therapeutic) application of exosomes in diverse biomedical fields

• Kim YS
• Ahn JS
• Kim S
• Kim HJ
• Kim SH
• Kang JS

• KMID: 2410101
• DOI: http://doi.org/10.4196/kjpp.2018.22.2.113

Abstract

Exosomes are membranous vesicles of 30-150 nm in diameter that are derived from the exocytosis of the intraluminal vesicles of many cell types including immune cells, stem cells, cardiovascular cells and tumor cells. Exosomes participate in intercellular communication by delivering their contents to recipient cells, with or without direct contact between cells, and thereby influence physiological and pathological processes. They are present in various body fluids and contain proteins, nucleic acids, lipids, and microRNAs that can be transported to surrounding cells. Theragnosis is a concept in next-generation medicine that simultaneously combines accurate diagnostics with therapeutic effects. Molecular components in exosomes have been found to be related to certain diseases and treatment responses, indicating that they may have applications in diagnosis via molecular imaging and biomarker detection. In addition, recent studies have reported that exosomes have immunotherapeutic applications or can act as a drug delivery system for targeted therapies with drugs and biomolecules. In this review, we describe the formation, structure, and physiological roles of exosomes. We also discuss their roles in the pathogenesis and progression of diseases including neurodegenerative diseases, cardiovascular diseases, and cancer. The potential applications of exosomes for theragnostic purposes in various diseases are also discussed. This review summarizes the current knowledge about the physiological and pathological roles of exosomes as well as their diagnostic and therapeutic uses, including emerging exosome-based therapies that could not be applied until now.

Keyword

Biomarker; Biomedical field; Drug delivery system; Exosome; Theragnostics

MeSH Terms

Body Fluids
Cardiovascular Diseases
Diagnosis
Drug Delivery Systems
Exocytosis
Exosomes*
MicroRNAs
Molecular Imaging
Neurodegenerative Diseases
Nucleic Acids
Pathologic Processes
Stem Cells
Therapeutic Uses
MicroRNAs
Nucleic Acids
Therapeutic Uses

Figure

• 

  Fig. 1 ESCRT-dependent or ESCRT-independent exosome biogenesis.

• 

  Fig. 2 The composition of cell-derived exosomes and interactions with recipient cells.

• 

  Fig. 3 Transportation of exosomes from 1) donor cells to 2) recipient cells. Exosomes are released from donor cells and uptake by recipient cells. The exosomes can be (a) fused with the plasma membrane or be (b) internalized by recipient cells. MVE, multivesicular endosome.

• 

  Fig. 4 Change of exosomal molecular compositions and cellular response against stress. HSPs, heat-shock proteins; P-gp, permeability glycoprotein.

Reference

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

2. Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci. 2016; 17:170.

3. Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience. 2015; 65:783–797.

4. Hurley JH. ESCRTs are everywhere. EMBO J. 2015; 34:2398–2407.

5. Huotari J, Helenius A. Endosome maturation. EMBO J. 2011; 30:3481–3500.

6. Xu W, Zeng S, Li M, Fan Z, Zhou B. Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription. J Biomed Res. 2016; 31:1–9.

7. Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014; 29:116–125.

8. Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell. 2011; 21:77–91.

9. McGough IJ, Vincent JP. Exosomes in developmental signalling. Development. 2016; 143:2482–2493.

10. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012; 14:677–685.

11. Andreu Z, Yáñez-Mó M. Tetraspanins in extracellular vesicle formation and function. Front Immunol. 2014; 5:442.

12. Yuyama K, Igarashi Y. Physiological and pathological roles of exosomes in the nervous system. Biomol Concepts. 2016; 7:53–68.

13. Madison MN, Okeoma CM. Exosomes: implications in HIV-1 pathogenesis. Viruses. 2015; 7:4093–4118.

14. Peterson MF, Otoc N, Sethi JK, Gupta A, Antes TJ. Integrated systems for exosome investigation. Methods. 2015; 87:31–45.

15. EL Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013; 12:347–357.

16. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2:569–579.

17. Andre F, Schartz NE, 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. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002; 360:295–305.

18. Hendrix A, Westbroek W, Bracke M, De Wever O. An ex(o)citing machinery for invasive tumor growth. Cancer Res. 2010; 70:9533–9537.

19. Zwicker JI, Liebman HA, Neuberg D, Lacroix R, Bauer KA, Furie BC, Furie B. Tumor-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res. 2009; 15:6830–6840.

20. Barry OP, Praticò D, Savani RC, FitzGerald GA. Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest. 1998; 102:136–144.

21. 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. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009; 284:34211–34222.

22. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008; 10:1470–1476.

23. Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014; 28:3–13.

24. de Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, Schiffelers RM, Gucek M, van Balkom BW. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 2012; 1:18396. DOI: 10.3402/jev.v1i0.18396.

25. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011; 71:5346–5356.

26. Peinado H, Alečkovič M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012; 18:883–891.

27. Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol. 2009; 183:3720–3730.

28. Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and upregulate biological activities of human regulatory T cells (Treg). PLoS One. 2010; 5:e11469.

29. Segura E, Guérin C, Hogg N, Amigorena S, Théry C. CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J Immunol. 2007; 179:1489–1496.

30. 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. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004; 104:3257–3266.

31. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011; 124:447–458.

32. Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001; 166:7309–7318.

33. 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.

34. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010; 4:214–222.

35. Bobrie A, Théry C. Unraveling the physiological functions of exosome secretion by tumors. Oncoimmunology. 2013; 2:e22565.

36. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009; 19:43–51.

37. Crescitelli R, Lässer C, Szabó TG, Kittel A, Eldh M, Dianzani I, Buzás EI, Lötvall J. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013; 2:DOI: 10.3402/jev.v2i0.20677.

38. 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. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012; 119:756–766.

39. Li J, Zhang Y, Liu Y, Dai X, Li W, Cai X, Yin Y, Wang Q, Xue Y, Wang C, Li D, Hou D, Jiang X, Zhang J, Zen K, Chen X, Zhang CY. Microvesicle-mediated transfer of microRNA-150 from monocytes to endothelial cells promotes angiogenesis. J Biol Chem. 2013; 288:23586–23596.

40. Skinner AM, O'Neill SL, Kurre P. Cellular microvesicle pathways can be targeted to transfer genetic information between non-immune cells. PLoS One. 2009; 4:e6219.

41. Hannafon BN, Ding WQ. Intercellular communication by exosome-derived microRNAs in cancer. Int J Mol Sci. 2013; 14:14240–14269.

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

43. Ahmad M, Iqbal M, Akhtar N, Murtaza G, Madni MA, Rasool F. Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in healthy and Escherichia coli induced febrile rabbits. Pakistan J Zool. 2010; 42:395–400.

44. Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity. Nat Immunol. 2004; 5:971–974.

45. Tanaka M, Oikawa K, Takanashi M, Kudo M, Ohyashiki J, Ohyashiki K, Kuroda M. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One. 2009; 4:e5532.

46. Tan M, Yan HB, Li JN, Li WK, Fu YY, Chen W, Zhou Z. Thrombin stimulated platelet-derived exosomes inhibit platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Cell Physiol Biochem. 2016; 38:2348–2365.

47. Khiljee S, Ahmad M, Murtaza G, Madni A, Akhtar N, Akhtar M. Bioequivalence evaluation of norfloxacin tablets based on in vitro - in vivo correlation. Pak J Pharm Sci. 2011; 24:421–426.

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

49. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ, Bernad A, Sánchez-Madrid F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011; 2:282.

50. Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol. 2011; 2011:842849.

51. Ahmad M, Ahmad R, Murtaza G. Comparative bioavailability and pharmacokinetics of flurbiprofen 200 mg SR pellets from India and France. Adv Clin Exp Med. 2011; 20:599–604.

52. Zhang HG, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol. 2014; 184:28–41.

53. Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep. 2015; 16:24–43.

54. El Andaloussi S, Lakhal S, Mäger I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev. 2013; 65:391–397.

55. Howitt J, Hill AF. Exosomes in the pathology of neurodegenerative diseases. J Biol Chem. 2016; 291:26589–26597.

56. Lakhter AJ, Sims EK. Minireview: emerging roles for extracellular vesicles in diabetes and related metabolic disorders. Mol Endocrinol. 2015; 29:1535–1548.

57. Stepanian A, Bourguignat L, Hennou S, Coupaye M, Hajage D, Salomon L, Alessi MC, Msika S, de Prost D. Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring). 2013; 21:2236–2243.

58. Cheng V, Kashyap SR, Schauer PR, Kirwan JP, McCrae KR. Restoration of glycemic control in patients with type 2 diabetes mellitus after bariatric surgery is associated with reduction in microparticles. Surg Obes Relat Dis. 2013; 9:207–212.

59. Suades R, Padró T, Badimon L. The role of blood-borne microparticles in inflammation and hemostasis. Semin Thromb Hemost. 2015; 41:590–606.

60. Amabile N, Cheng S, Renard JM, Larson MG, Ghorbani A, Mc-Cabe E, Griffin G, Guerin C, Ho JE, Shaw SY, Cohen KS, Vasan RS, Tedgui A, Boulanger CM, Wang TJ. Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham Heart Study. Eur Heart J. 2014; 35:2972–2979.

61. Lawson C, Vicencio JM, Yellon DM, Davidson SM. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol. 2016; 228:R57–R71.

62. Yang C, Robbins PD. Immunosuppressive exosomes: a new approach for treating arthritis. Int J Rheumatol. 2012; 2012:573528.

63. Tran TH, Nguyen HT, Pham TT, Choi JY, Choi HG, Yong CS, Kim JO. Development of a graphene oxide nanocarrier for dual-drug chemo-phototherapy to overcome drug resistance in cancer. ACS Appl Mater Interface. 2015; 7:28647–28655.

64. Pisitkun T, Johnstone R, Knepper MA. Discovery of urinary biomarkers. Mol Cell Proteomics. 2006; 5:1760–1771.

65. Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009; 6:267–283.

66. Runz S, Keller S, Rupp C, Stoeck A, Issa Y, Koensgen D, Mustea A, Sehouli J, Kristiansen G, Altevogt P. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecol Oncol. 2007; 107:563–571.

67. Lässer C, Alikhani VS, Ekström K, Eldh M, Paredes PT, Bossios A, Sjöstrand M, Gabrielsson S, Lötvall J, Valadi H. Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. J Transl Med. 2011; 9:9.

68. Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, Hager HD, Abdel-Bakky MS, Gutwein P, Altevogt P. CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int. 2007; 72:1095–1102.

69. Taylor DD, Homesley HD, Doellgast GJ. “Membrane-associated” immunoglobulins in cyst and ascites fluids of ovarian cancer patients. Am J Reprod Immunol. 1983; 3:7–11.

70. Logozzi M, De Milito A, Lugini L, Borghi M, Calabrò L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, Santinami M, Huber V, Maio M, Rivoltini L, Fais S. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009; 4:e5219.

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

72. Qu JL, Qu XJ, Zhao MF, Teng YE, Zhang Y, Hou KZ, Jiang YH, Yang XH, Liu YP. Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation. Dig Liver Dis. 2009; 41:875–880.

73. McCready J, Sims JD, Chan D, Jay DG. Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer. 2010; 10:294.

74. Jung T, Catalgol B, Grune T. The proteasomal system. Mol Aspects Med. 2009; 30:191–296.

75. Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, Le Pecq JB. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods. 2002; 270:211–226.

76. Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A, Hsu DH, Le Pecq JB, Lyerly HK. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005; 3:9.

77. Yoshioka Y, Konishi Y, Kosaka N, Katsuda T, Kato T, Ochiya T. Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles. 2013; 2:DOI: 10.3402/jev.v2i0.20424.

78. Smalley DM, Sheman NE, Nelson K, Theodorescu D. Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J Proteome Res. 2008; 7:2088–2096.

79. Chen CL, Lai YF, Tang P, Chien KY, Yu JS, Tsai CH, Chen HW, Wu CC, Chung T, Hsu CW, Chen CD, Chang YS, Chang PL, Chen YT. Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. J Proteome Res. 2012; 11:5611–5629.

80. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008; 105:10513–10518.

81. Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, Steuber T, Beissbarth T, Kuner R, Sültmann H. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011; 128:608–616.

82. Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, Xiao T, Schafer J, Lee ML, Schmittgen TD, Nana-Sinkam SP, Jarjoura D, Marsh CB. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One. 2008; 3:e3694.

83. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF, Wang XZ. Exosomes: novel biomarkers for clinical diagnosis. ScientificWorldJournal. 2015; 2015.

84. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, Widmark A. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009; 100:1603–1607.

85. Tanaka Y, Kamohara H, Kinoshita K, Kurashige J, Ishimoto T, Iwatsuki M, Watanabe M, Baba H. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013; 119:1159–1167.

86. Takeshita N, Hoshino I, Mori M, Akutsu Y, Hanari N, Yoneyama Y, Ikeda N, Isozaki Y, Maruyama T, Akanuma N, Komatsu A, Jitsukawa M, Matsubara H. 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.

87. Kuwabara Y, Ono K, Horie T, Nishi H, Nagao K, Kinoshita M, Watanabe S, Baba O, Kojima Y, Shizuta S, Imai M, Tamura T, Kita T, Kimura T. Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ Cardiovasc Genet. 2011; 4:446–454.

88. Lv LL, Cao YH, Ni HF, Xu M, Liu D, Liu H, Chen PS, Liu BC. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am J Physiol Renal Physiol. 2013; 305:F1220–F1227.

89. Zhou H, Yuen PS, Pisitkun T, Gonzales PA, Yasuda H, Dear JW, Gross P, Knepper MA, Star RA. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int. 2006; 69:1471–1476.

90. Zhou H, Xu M, Huang Q, Gates AT, Zhang XD, Castle JC, Stec E, Ferrer M, Strulovici B, Hazuda DJ, Espeseth AS. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe. 2008; 4:495–504.

91. Takata K, Matsuzaki T, Tajika Y, Ablimit A, Hasegawa T. Localization and trafficking of aquaporin 2 in the kidney. Histochem Cell Biol. 2008; 130:197–209.

92. Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One. 2010; 5:e8577.

93. Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012; 3:359.

94. Chen TS, Yeo RWY, Arslan F, Yin Y, Tan SS, Lai RC, Choo A, Padmanabhan J, Lee CN, de Kleijn DPV, Tan KH, Lim SK. Efficiency of exosome production correlates inversely with the developmental maturity of MSC donor. J Stem Cell Res Ther. 2013; 3:145.

95. André F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH, Tursz T, Amigorena S, Angevin E, Zitvogel L. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. 2004; 172:2126–2136.

96. Hsu DH, Paz P, Villaflor G, Rivas A, Mehta-Damani A, Angevin E, Zitvogel L, Le Pecq JB. Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides. J Immunother. 2003; 26:440–450.

97. Chaput N, Schartz NE, André F, Taïeb J, Novault S, Bonnaventure P, Aubert N, Bernard J, Adema G, Adams M, Ferrantini M, Carpentier AF, Escudier B, Tursz T, Angevin E, Zitvogel L. Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. J Immunol. 2004; 172:2137–2146.

98. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012; 126:2601–2611.

99. Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015; 4:1131–1143.

100. Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, Xiong Y. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015; 122:856–867.

101. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012; 30:1556–1564.

102. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009; 20:1053–1067.

103. Li T, Zhu J, Ma K, Liu N, Feng K, Li X, Wang S, Bie P. Autologous bone marrow-derived mesenchymal stem cell transplantation promotes liver regeneration after portal vein embolization in cirrhotic rats. J Surg Res. 2013; 184:1161–1173.

104. Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY, Kim CW. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One. 2013; 8:e84256.

105. Yang Y, Bucan V, Baehre H, von der, Otte A, Hass R. Acquisition of new tumor cell properties by MSC-derived exosomes. Int J Oncol. 2015; 47:244–252.

106. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014; 28:970–973.

107. Rahman MJ, Regn D, Bashratyan R, Dai YD. Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes. 2014; 63:1008–1020.

108. Zöller M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer. 2009; 9:40–55.

109. Pap E, Pállinger E, Pásztói M, Falus A. Highlights of a new type of intercellular communication: microvesicle-based information transfer. Inflamm Res. 2009; 58:1–8.

110. Taylor DD, Gercel-Taylor C. Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol. 2011; 33:441–454.

111. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF. IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010; 363:411–422.

112. Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, Le Chevalier T, Livartoski A, Barlesi F, Laplanche A, Ploix S, Vimond N, Peguillet I, Théry C, Lacroix L, Zoernig I, Dhodapkar K, Dhodapkar M, Viaud S, Soria JC, Reiners KS, Pogge von, Vély F, Rusakiewicz S, Eggermont A, Pitt JM, Zitvogel L, Chaput N. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology. 2015; 5:e1071008.

113. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T. LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008; 26:3552–3559.

114. Polo V, Garcia-Martin E, Bambo MP, Pinilla J, Larrosa JM, Satue M, Otin S, Pablo LE. Reliability and validity of Cirrus and Spectralis optical coherence tomography for detecting retinal atrophy in Alzheimer's disease. Eye (Lond). 2014; 28:680–690.

115. Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, Amigorena S, Théry C. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. 2005; 106:216–223.

116. Utsugi-Kobukai S, Fujimaki H, Hotta C, Nakazawa M, Minami M. MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol Lett. 2003; 89:125–131.

117. Viaud S, Ploix S, Lapierre V, Théry C, Commere PH, Tramalloni D, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L, Chaput N. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-γ. J Immunother. 2011; 34:65–75.

118. Gutiérrez-Vázquez C, Villarroya-Beltri C, Mittelbrunn M, Sánchez-Madrid F. Transfer of extracellular vesicles during immune cell-cell interactions. Immunol Rev. 2013; 251:125–142.

119. 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. 2011; 6:e16899.

120. Biasutto L, Chiechi A, Couch R, Liotta LA, Espina V. Retinal pigment epithelium (RPE) exosomes contain signaling phosphoproteins affected by oxidative stress. Exp Cell Res. 2013; 319:2113–2123.

121. Eldh M, Ekström K, Valadi H, Sjöstrand M, Olsson B, Jernås M, Lötvall J. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One. 2010; 5:e15353.

122. Zhang Y, Luo CL, He BC, Zhang JM, Cheng G, Wu XH. Exosomes derived from IL-12-anchored renal cancer cells increase induction of specific antitumor response in vitro: a novel vaccine for renal cell carcinoma. Int J Oncol. 2010; 36:133–140.

123. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29:341–345.

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

125. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010; 31:27–36.

126. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, Miller D, Zhang HG. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011; 19:1769–1779.

127. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010; 18:1606–1614.

128. van Dommelen SM, Vader P, Lakhal S, Kooijmans SA, van Solinge WW, Wood MJ, Schiffelers RM. Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. J Control Release. 2012; 161:635–644.

129. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, Nilsson J, Lötvall J, Kim YK, Gho YS. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano. 2013; 7:7698–7710.