Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes

Cells - Tập 8 Số 4 - Trang 307
Sangiliyandi Gurunathan1, Min-Hee Kang1, Muniyandi Jeyaraj1, Muhammad Qasim1, Jin‐Hoi Kim1
1Department of Stem Cell and Regenerative Biotechnology, Konkuk University, 1 Hwayang-Dong, Gwangin-gu, Seoul 05029, Korea

Tóm tắt

Exosomes are extracellular vesicles that contain a specific composition of proteins, lipids, RNA, and DNA. They are derived from endocytic membranes and can transfer signals to recipient cells, thus mediating a novel mechanism of cell-to-cell communication. They are also thought to be involved in cellular waste disposal. Exosomes play significant roles in various biological functions, including the transfer of biomolecules such as RNA, proteins, enzymes, and lipids and the regulation of numerous physiological and pathological processes in various diseases. Because of these properties, they are considered to be promising biomarkers for the diagnosis and prognosis of various diseases and may contribute to the development of minimally invasive diagnostics and next generation therapies. The biocompatible nature of exosomes could enhance the stability and efficacy of imaging probes and therapeutics. Due to their potential use in clinical applications, exosomes have attracted much research attention on their roles in health and disease. To explore the use of exosomes in the biomedical arena, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are well-understood. Herein, we discuss the history, biogenesis, release, isolation, characterization, and biological functions of exosomes, as well as the factors influencing their biogenesis and their technical and biological challenges. We conclude this review with a discussion on the future perspectives of exosomes.

Từ khóa


Tài liệu tham khảo

Raposo, 2013, Extracellular vesicles: Exosomes, microvesicles, and friends, J. Cell Biol., 200, 373, 10.1083/jcb.201211138

Holme, 1994, Demonstration of platelet-derived microvesicles in blood from patients with activated coagulation and fibrinolysis using a filtration technique and western blotting, Thromb. Haemost., 72, 666, 10.1055/s-0038-1648939

Hess, 1999, Ectosomes released by human neutrophils are specialized functional units, J. Immunol., 163, 4564, 10.4049/jimmunol.163.8.4564

Cocucci, 2009, Shedding microvesicles: Artefacts no more, Trends Cell Biol., 19, 43, 10.1016/j.tcb.2008.11.003

Gyorgy, 2011, Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters, Blood, 117, e39, 10.1182/blood-2010-09-307595

Simons, 2009, Exosomes--vesicular carriers for intercellular communication, Curr. Opin. Cell Biol., 21, 575, 10.1016/j.ceb.2009.03.007

Thery, 2009, Membrane vesicles as conveyors of immune responses, Nat. Rev. Immunol., 9, 581, 10.1038/nri2567

Simpson, 2008, Proteomic profiling of exosomes: Current perspectives, Proteomics, 8, 4083, 10.1002/pmic.200800109

Properzi, 2013, Exosomes: The future of biomarkers in medicine, Biomark. Med., 7, 769, 10.2217/bmm.13.63

Thery, 2006, Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Curr. Protoc. Cell Biol., 30, 3, 10.1002/0471143030.cb0322s30

Clayton, 2001, Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry, J. Immunol. Methods, 247, 163, 10.1016/S0022-1759(00)00321-5

Dragovic, 2011, Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis, Nanomedicine, 7, 780, 10.1016/j.nano.2011.04.003

Simoes, 2006, Exosomes: A common pathway for a specialized function, J. Biochem., 140, 13, 10.1093/jb/mvj128

Zoller, 2009, Tetraspanins: Push and pull in suppressing and promoting metastasis, Nat. Rev. Cancer, 9, 40, 10.1038/nrc2543

Thery, 1999, Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73, J. Cell Biol., 147, 599, 10.1083/jcb.147.3.599

Wubbolts, 2003, Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation, J. Biol. Chem., 278, 10963, 10.1074/jbc.M207550200

Wilson, 2004, Secretion of intracellular IL-1 receptor antagonist (type 1) is dependent on P2X7 receptor activation, J. Immunol., 173, 1202, 10.4049/jimmunol.173.2.1202

Heijnen, 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, 10.1182/blood.V94.11.3791

Obregon, 2006, Exovesicles from human activated dendritic cells fuse with resting dendritic cells, allowing them to present alloantigens, Am. J. Pathol., 169, 2127, 10.2353/ajpath.2006.060453

Arkesteijn, 2013, Dynamics of dendritic cell-derived vesicles: High-resolution flow cytometric analysis of extracellular vesicle quantity and quality, J. Leukoc. Biol., 93, 395

Savina, 2005, Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner, Traffic, 6, 131, 10.1111/j.1600-0854.2004.00257.x

Raposo, 1997, Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation, Mol. Biol. Cell, 8, 2631, 10.1091/mbc.8.12.2631

Rana, 2012, Toward tailored exosomes: The exosomal tetraspanin web contributes to target cell selection, Int. J. Biochem. Cell Biol., 44, 1574, 10.1016/j.biocel.2012.06.018

Hemler, 2003, Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain, Annu. Rev. Cell Dev. Biol., 19, 397, 10.1146/annurev.cellbio.19.111301.153609

Harding, 2013, Exosomes: Looking back three decades and into the future, J. Cell Biol., 200, 367, 10.1083/jcb.201212113

Bobrie, 2011, Exosome secretion: Molecular mechanisms and roles in immune responses, Traffic, 12, 1659, 10.1111/j.1600-0854.2011.01225.x

Rak, 2010, Microparticles in cancer, Semin. Thromb. Hemost., 36, 888, 10.1055/s-0030-1267043

Hood, 2011, Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis, Cancer Res., 71, 3792, 10.1158/0008-5472.CAN-10-4455

Zhang, 2011, Exosomes and cancer: A newly described pathway of immune suppression, Clin. Cancer Res., 17, 959, 10.1158/1078-0432.CCR-10-1489

Kujala, P., Raymond, C.R., Romeijn, M., Godsave, S.F., van Kasteren, S.I., Wille, H., Prusiner, S.B., Mabbott, N.A., and Peters, P.J. (2011). Prion uptake in the gut: Identification of the first uptake and replication sites. PLoS Pathog., 7.

Chargaff, 1946, The biological significance of the thromboplastic protein of blood, J. Biol. Chem., 166, 189, 10.1016/S0021-9258(17)34997-9

Wieme, 1977, Spontaneous shedding of plasma membrane fragments by human cells in vivo and in vitro, Clin. Chim. Acta, 81, 237, 10.1016/0009-8981(77)90054-7

Wolf, 1967, The nature and significance of platelet products in human plasma, Br. J. Haematol., 13, 269, 10.1111/j.1365-2141.1967.tb08741.x

Trams, 1981, Exfoliation of membrane ecto-enzymes in the form of micro-vesicles, Biochim. Biophys. Acta, 645, 63, 10.1016/0005-2736(81)90512-5

Harding, 1984, Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: Demonstration of a pathway for receptor shedding, Eur. J. Cell Biol., 35, 256

Pan, 1985, Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes, J. Cell Biol., 101, 942, 10.1083/jcb.101.3.942

Raposo, 1996, B lymphocytes secrete antigen-presenting vesicles, J. Exp. Med., 183, 1161, 10.1084/jem.183.3.1161

Zitvogel, 1998, Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes, Nat. Med., 4, 594, 10.1038/nm0598-594

Harding, 1983, Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes, J. Cell Biol., 97, 329, 10.1083/jcb.97.2.329

Colombo, 2014, Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles, Annu. Rev. Cell Dev. Biol., 30, 255, 10.1146/annurev-cellbio-101512-122326

Batista, 2011, Identification of a conserved glycan signature for microvesicles, J. Proteome Res., 10, 4624, 10.1021/pr200434y

Cocucci, 2015, Ectosomes and exosomes: Shedding the confusion between extracellular vesicles, Trends Cell Biol., 25, 364, 10.1016/j.tcb.2015.01.004

Hessvik, 2018, Current knowledge on exosome biogenesis and release, Cell. Mol. Life Sci., 75, 193, 10.1007/s00018-017-2595-9

Henne, 2013, Molecular mechanisms of the membrane sculpting ESCRT pathway, Cold Spring Harb. Perspect. Biol., 5, a016766, 10.1101/cshperspect.a016766

Zhu, 2013, Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes, Mol. Biol. Cell, 24, 1619, 10.1091/mbc.e12-07-0544

Stuffers, 2009, Multivesicular endosome biogenesis in the absence of ESCRTs, Traffic, 10, 925, 10.1111/j.1600-0854.2009.00920.x

McMahon, 2015, Membrane curvature at a glance, J. Cell Sci., 128, 1065, 10.1242/jcs.114454

Trajkovic, 2008, Ceramide triggers budding of exosome vesicles into multivesicular endosomes, Science, 319, 1244, 10.1126/science.1153124

Embade, 2008, Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes, J. Proteome Res., 7, 5157, 10.1021/pr8004887

Subra, 2010, Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins, J. Lipid Res., 51, 2105, 10.1194/jlr.M003657

Seow, 2011, Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes, Nat. Biotechnol., 29, 341, 10.1038/nbt.1807

Gurunathan, 2000, Yeast exocytic v-SNAREs confer endocytosis, Mol. Biol. Cell, 11, 3629, 10.1091/mbc.11.10.3629

Gurunathan, 2002, t-SNARE phosphorylation regulates endocytosis in yeast, Mol. Biol. Cell, 13, 1594, 10.1091/mbc.01-11-0541

Mobius, 2003, Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway, Traffic, 4, 222, 10.1034/j.1600-0854.2003.00072.x

Valadi, 2007, Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat. Cell Biol., 9, 654, 10.1038/ncb1596

Keerthikumar, 2016, ExoCarta: A Web-Based Compendium of Exosomal Cargo, J. Mol. Biol., 428, 688, 10.1016/j.jmb.2015.09.019

Dickens, 2017, Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions, Sci. Signal., 10, eaai7696, 10.1126/scisignal.aai7696

Howitt, 2016, Exosomes in the Pathology of Neurodegenerative Diseases, J. Biol. Chem., 291, 26589, 10.1074/jbc.R116.757955

Tian, 2014, A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy, Biomaterials, 35, 2383, 10.1016/j.biomaterials.2013.11.083

Chen, 2011, Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs, J. Transl. Med., 9, 47, 10.1186/1479-5876-9-47

Yeo, 2013, Mesenchymal stem cell: An efficient mass producer of exosomes for drug delivery, Adv. Drug Deliv. Rev., 65, 336, 10.1016/j.addr.2012.07.001

Gal, 1981, Effect of cell density and confluency on cholesterol metabolism in cancer cells in monolayer culture, Cancer Res., 41, 473

Steinman, 2003, Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2, Oncogene, 22, 3608, 10.1038/sj.onc.1206523

Hayes, 2005, Cell confluency is as efficient as serum starvation for inducing arrest in the G0/G1 phase of the cell cycle in granulosa and fibroblast cells of cattle, Anim. Reprod. Sci., 87, 181, 10.1016/j.anireprosci.2004.11.011

Savina, 2003, Exosome release is regulated by a calcium-dependent mechanism in K562 cells, J. Biol. Chem., 278, 20083, 10.1074/jbc.M301642200

Svensson, 2011, Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells, Proc. Natl. Acad. Sci. USA, 108, 13147, 10.1073/pnas.1104261108

King, H.W., Michael, M.Z., and Gleadle, J.M. (2012). Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 12.

Kucharzewska, 2013, Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development, Proc. Natl. Acad. Sci. USA, 110, 7312, 10.1073/pnas.1220998110

Koumangoye, R.B., Sakwe, A.M., Goodwin, J.S., Patel, T., and Ochieng, J. (2011). Detachment of breast tumor cells induces rapid secretion of exosomes which subsequently mediate cellular adhesion and spreading. PLoS ONE, 6.

Lund, 2009, Effect of growth media and serum replacements on the proliferation and differentiation of adipose-derived stem cells, Cytotherapy, 11, 189, 10.1080/14653240902736266

Bryan, 2011, Elucidating the contribution of the elemental composition of fetal calf serum to antigenic expression of primary human umbilical-vein endothelial cells in vitro, Biosci. Rep., 31, 199, 10.1042/BSR20100064

Verhaar, 2012, Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes, J. Extracell. Vesicles, 1, 18396, 10.3402/jev.v1i0.18396

Li, 2015, Serum-free culture alters the quantity and protein composition of neuroblastoma-derived extracellular vesicles, J. Extracell. Vesicles, 4, 26883, 10.3402/jev.v4.26883

Peterson, 2015, Integrated systems for exosome investigation, Methods, 87, 31, 10.1016/j.ymeth.2015.04.015

Witwer, 2013, Standardization of sample collection, isolation and analysis methods in extracellular vesicle research, J. Extracell. Vesicles, 2, 20360, 10.3402/jev.v2i0.20360

Mestdagh, 2014, The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling, J. Extracell. Vesicles, 3, 24858, 10.3402/jev.v3.24858

Li, 2017, Progress in Exosome Isolation Techniques, Theranostics, 7, 789, 10.7150/thno.18133

Zeringer, 2015, Strategies for isolation of exosomes, Cold Spring Harb. Protoc., 2015, 319, 10.1101/pdb.top074476

Balaj, 2012, Impact of biofluid viscosity on size and sedimentation efficiency of the isolated microvesicles, Front. Physiol., 3, 162

Sabapatha, 2006, Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences, Am. J. Reprod. Immunol., 56, 345, 10.1111/j.1600-0897.2006.00435.x

Alvarez, 2012, Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers, Kidney Int., 82, 1024, 10.1038/ki.2012.256

Lai, 2010, Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Stem Cell Res., 4, 214, 10.1016/j.scr.2009.12.003

Ibrahim, 2014, Exosomes as critical agents of cardiac regeneration triggered by cell therapy, Stem Cell Rep., 2, 606, 10.1016/j.stemcr.2014.04.006

Tauro, 2012, Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes, Methods, 56, 293, 10.1016/j.ymeth.2012.01.002

Grasso, 2015, Molecular screening of cancer-derived exosomes by surface plasmon resonance spectroscopy, Anal. Bioanal. Chem., 407, 5425, 10.1007/s00216-015-8711-5

Zarovni, 2015, Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches, Methods, 87, 46, 10.1016/j.ymeth.2015.05.028

Hong, C.S., Muller, L., Boyiadzis, M., and Whiteside, T.L. (2014). Isolation and characterization of CD34+ blast-derived exosomes in acute myeloid leukemia. PLoS ONE, 9.

Lee, 2015, Acoustic purification of extracellular microvesicles, ACS Nano, 9, 2321, 10.1021/nn506538f

Davies, 2012, Microfluidic filtration system to isolate extracellular vesicles from blood, Lab Chip, 12, 5202, 10.1039/c2lc41006k

Wu, 2017, Microfluidics for exosome isolation and analysis: Enabling liquid biopsy for personalized medicine, Lab Chip, 17, 3558, 10.1039/C7LC00592J

Chen, 2010, Microfluidic isolation and transcriptome analysis of serum microvesicles, Lab Chip, 10, 505, 10.1039/B916199F

Wang, 2013, Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles, Lab Chip, 13, 2879, 10.1039/c3lc41343h

Kanwar, 2014, Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes, Lab Chip, 14, 1891, 10.1039/C4LC00136B

Ashcroft, 2012, Determination of the size distribution of blood microparticles directly in plasma using atomic force microscopy and microfluidics, Biomed. Microdevices, 14, 641, 10.1007/s10544-012-9642-y

Shao, 2015, Diagnostic technologies for circulating tumour cells and exosomes, Biosci. Rep., 36, e00292, 10.1042/BSR20150180

Gonda, 2018, A practical approach to extracellular vesicle characterization among similar biological samples, Biomed. Phys. Eng. Express, 4, 065013, 10.1088/2057-1976/aad6d8

Szatanek, R., Baj-Krzyworzeka, M., Zimoch, J., Lekka, M., Siedlar, M., and Baran, J. (2017). The Methods of Choice for Extracellular Vesicles (EVs) Characterization. Int. J. Mol. Sci., 18.

Bryant, 1996, Improved particle size distribution measurements using multiangle dynamic light scattering. 2. Refinements and applications, Langmuir, 12, 6224, 10.1021/la960224o

Hoo, 2008, A comparison of atomic force microscopy (AFM) and dynamic light scattering (DLS) methods to characterize nanoparticle size distributions, J. Nanopart. Res., 10, 89, 10.1007/s11051-008-9435-7

Lawrie, 2009, Microparticle sizing by dynamic light scattering in fresh-frozen plasma, Vox Sang., 96, 206, 10.1111/j.1423-0410.2008.01151.x

Atay, 2012, Nanoparticle analysis of circulating cell-derived vesicles in ovarian cancer patients, Anal. Biochem., 428, 44, 10.1016/j.ab.2012.06.004

Anderson, 2015, Observations of Tunable Resistive Pulse Sensing for Exosome Analysis: Improving System Sensitivity and Stability, Langmuir, 31, 6577, 10.1021/acs.langmuir.5b01402

Vogel, 2017, High-Resolution Single Particle Zeta Potential Characterisation of Biological Nanoparticles using Tunable Resistive Pulse Sensing, Sci. Rep., 7, 17479, 10.1038/s41598-017-14981-x

Patko, 2013, Label-free optical monitoring of surface adhesion of extracellular vesicles by grating coupled interferometry, Sens. Actuators B Chem., 188, 697, 10.1016/j.snb.2013.07.035

Shimbo, 2014, Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration, Biochem. Biophys. Res. Commun., 445, 381, 10.1016/j.bbrc.2014.02.007

Katsuda, 2013, The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles, Proteomics, 13, 1637, 10.1002/pmic.201200373

Binnig, 1986, Atomic force microscope, Phys. Rev. Lett., 56, 930, 10.1103/PhysRevLett.56.930

Yuana, 2010, Atomic force microscopy: A novel approach to the detection of nanosized blood microparticles, J. Thromb. Haemost., 8, 315, 10.1111/j.1538-7836.2009.03654.x

Sharma, 2017, Tumor-derived exosomes in ovarian cancer—Liquid biopsies for early detection and real-time monitoring of cancer progression, Oncotarget, 8, 104687, 10.18632/oncotarget.22191

Hardij, J., Cecchet, F., Berquand, A., Gheldof, D., Chatelain, C., Mullier, F., Chatelain, B., and Dogne, J.M. (2013). Characterisation of tissue factor-bearing extracellular vesicles with AFM: Comparison of air-tapping-mode AFM and liquid Peak Force AFM. J. Extracell. Vesicles, 2.

Sharma, 2010, Structural-mechanical characterization of nanoparticle exosomes in human saliva, using correlative AFM, FESEM, and force spectroscopy, ACS Nano, 4, 1921, 10.1021/nn901824n

Zaborowski, 2015, Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study, Bioscience, 65, 783, 10.1093/biosci/biv084

Pospichalova, 2015, Simplified protocol for flow cytometry analysis of fluorescently labeled exosomes and microvesicles using dedicated flow cytometer, J. Extracell. Vesicles, 4, 25530, 10.3402/jev.v4.25530

Suarez, 2017, A bead-assisted flow cytometry method for the semi-quantitative analysis of Extracellular Vesicles, Sci. Rep., 7, 11271, 10.1038/s41598-017-11249-2

Stoorvogel, 2012, Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry, Nat. Protoc., 7, 1311, 10.1038/nprot.2012.065

Erdbrugger, 2014, Imaging flow cytometry elucidates limitations of microparticle analysis by conventional flow cytometry, Cytom. A, 85, 756, 10.1002/cyto.a.22494

Chandler, 2011, A new microparticle size calibration standard for use in measuring smaller microparticles using a new flow cytometer, J. Thromb. Haemost., 9, 1216, 10.1111/j.1538-7836.2011.04283.x

Orozco, 2010, Flow cytometric analysis of circulating microparticles in plasma, Cytom. A, 77, 502, 10.1002/cyto.a.20886

Smith, 2015, Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content, J. Extracell. Vesicles, 4, 28533, 10.3402/jev.v4.28533

He, 2014, Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology, Lab Chip, 14, 3773, 10.1039/C4LC00662C

Ramirez, 2018, Extracellular vesicles: Mediators and biomarkers of pathology along CNS barriers, Fluids Barriers CNS, 15, 19, 10.1186/s12987-018-0104-7

Thery, 2002, Exosomes: Composition, biogenesis and function, Nat. Rev. Immunol., 2, 569, 10.1038/nri855

Adams, 2007, Molecular regulation of angiogenesis and lymphangiogenesis, Nat. Rev. Mol. Cell Biol., 8, 464, 10.1038/nrm2183

Bazigou, 2013, Flow control in our vessels: Vascular valves make sure there is no way back, Cell. Mol. Life Sci., 70, 1055, 10.1007/s00018-012-1110-6

Kaur, 2014, CD47 signaling regulates the immunosuppressive activity of VEGF in T cells, J. Immunol., 193, 3914, 10.4049/jimmunol.1303116

Hood, 2009, Paracrine induction of endothelium by tumor exosomes, Lab. Investig., 89, 1317, 10.1038/labinvest.2009.94

Zhou, 2014, Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis, Cancer Cell, 25, 501, 10.1016/j.ccr.2014.03.007

Ma, 2018, MicroRNA-132, Delivered by Mesenchymal Stem Cell-Derived Exosomes, Promote Angiogenesis in Myocardial Infarction, Stem Cells Int., 2018, 3290372, 10.1155/2018/3290372

Atay, 2011, Trophoblast-derived exosomes mediate monocyte recruitment and differentiation, Am. J. Reprod. Immunol., 65, 65, 10.1111/j.1600-0897.2010.00880.x

Sidhu, 2004, The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions, Oncogene, 23, 956, 10.1038/sj.onc.1207070

Grange, 2011, Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche, Cancer Res., 71, 5346, 10.1158/0008-5472.CAN-11-0241

Vrijsen, 2010, Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells, J. Cell Mol. Med., 14, 1064

Zhu, 2012, Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo, Cancer Lett., 315, 28, 10.1016/j.canlet.2011.10.002

Cantaluppi, 2012, Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets, Cell Transplant., 21, 1305, 10.3727/096368911X627534

Chen, 2010, Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs, Nucleic Acids Res., 38, 215, 10.1093/nar/gkp857

Yoo, 2012, Discovery and characterization of novel microRNAs during endothelial differentiation of human embryonic stem cells, Stem Cells Dev., 21, 2049, 10.1089/scd.2011.0500

Zhang, 2015, HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing, Stem Cells, 33, 2158, 10.1002/stem.1771

Nakamura, 2015, Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration, FEBS Lett., 589, 1257, 10.1016/j.febslet.2015.03.031

Barcia, 2016, Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells, J. Cell Mol. Med., 20, 1457, 10.1111/jcmm.12834

Ribatti, 2012, Cancer stem cells and tumor angiogenesis, Cancer Lett., 321, 13, 10.1016/j.canlet.2012.02.024

Sugimori, M., Hayakawa, Y., Boman, B.M., Fields, J.Z., Awaji, M., Kozano, H., Tamura, R., Yamamoto, S., Ogata, T., and Yamada, M. (2015). Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations. PLoS ONE, 10.

Sun, 2017, Glioma stem cells-derived exosomes promote the angiogenic ability of endothelial cells through miR-21/VEGF signal, Oncotarget, 8, 36137, 10.18632/oncotarget.16661

Conigliaro, 2015, CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA, Mol. Cancer, 14, 155, 10.1186/s12943-015-0426-x

Zuniga, 2016, Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Angiogenesis: Potencial Clinical Application, Front. Physiol., 7, 24

Kerr, 1972, Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics, Br. J. Cancer, 26, 239, 10.1038/bjc.1972.33

Thery, 2001, Proteomic analysis of dendritic cell-derived exosomes: A secreted subcellular compartment distinct from apoptotic vesicles, J. Immunol., 166, 7309, 10.4049/jimmunol.166.12.7309

Gregory, 2010, Microenvironmental influences of apoptosis in vivo and in vitro, Apoptosis, 15, 1029, 10.1007/s10495-010-0485-9

Caruso, 2018, Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris, Front. Immunol., 9, 1486, 10.3389/fimmu.2018.01486

Poon, 2017, Disassembly of the Dying: Mechanisms and Functions, Trends Cell Biol., 27, 151, 10.1016/j.tcb.2016.08.011

Tixeira, 2015, A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure, Nat. Commun., 6, 7439, 10.1038/ncomms8439

Vallabhaneni, K.C., Hassler, M.Y., Abraham, A., Whitt, J., Mo, Y.Y., Atfi, A., and Pochampally, R. (2016). Mesenchymal Stem/Stromal Cells under Stress Increase Osteosarcoma Migration and Apoptosis Resistance via Extracellular Vesicle Mediated Communication. PLoS ONE, 11.

Zaharie, 2015, Exosome-Carried microRNA-375 Inhibits Cell Progression and Dissemination via Bcl-2 Blocking in Colon Cancer, J. Gastrointest. Liver Dis., 24, 435, 10.15403/jgld.2014.1121.244.375

Clayton, 2008, Human tumor-derived exosomes down-modulate NKG2D expression, J. Immunol., 180, 7249, 10.4049/jimmunol.180.11.7249

Andreola, 2002, Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles, J. Exp. Med., 195, 1303, 10.1084/jem.20011624

Lehmann, 2008, Senescence-associated exosome release from human prostate cancer cells, Cancer Res., 68, 7864, 10.1158/0008-5472.CAN-07-6538

Aharon, 2008, Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells, Thromb. Haemost., 100, 878, 10.1160/TH07-11-0691

Bruno, 2013, Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth, Stem Cells Dev., 22, 758, 10.1089/scd.2012.0304

Shenoda, 2016, Modulation of Immune Responses by Exosomes Derived from Antigen-Presenting Cells, Clin. Med. Insights Pathol., 9, 1

Bianchi, 2007, DAMPs, PAMPs and alarmins: All we need to know about danger, J. Leukoc. Biol., 81, 1, 10.1189/jlb.0306164

Mogensen, 2009, Pathogen recognition and inflammatory signaling in innate immune defenses, Clin. Microbiol. Rev., 22, 240, 10.1128/CMR.00046-08

McCall, 2011, Epigenetics, bioenergetics, and microRNA coordinate gene-specific reprogramming during acute systemic inflammation, J. Leukoc. Biol., 90, 439, 10.1189/jlb.0211075

McDonald, 2014, Functional significance of macrophage-derived exosomes in inflammation and pain, Pain, 155, 1527, 10.1016/j.pain.2014.04.029

Choudhuri, 2014, Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse, Nature, 507, 118, 10.1038/nature12951

Siljander, 2015, Biological properties of extracellular vesicles and their physiological functions, J. Extracell. Vesicles, 4, 27066, 10.3402/jev.v4.27066

Segura, 2005, Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses, Blood. Cells Mol. Dis., 35, 89, 10.1016/j.bcmd.2005.05.003

Admyre, 2006, Direct exosome stimulation of peripheral human T cells detected by ELISPOT, Eur. J. Immunol., 36, 1772, 10.1002/eji.200535615

Lindenbergh, 2018, Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells, Annu. Rev. Immunol., 36, 435, 10.1146/annurev-immunol-041015-055700

Colino, 2006, Exosomes from bone marrow dendritic cells pulsed with diphtheria toxoid preferentially induce type 1 antigen-specific IgG responses in naive recipients in the absence of free antigen, J. Immunol., 177, 3757, 10.4049/jimmunol.177.6.3757

Gallego, 2011, Induction of protective immunity against Eimeria tenella infection using antigen-loaded dendritic cells (DC) and DC-derived exosomes, Vaccine, 29, 3818, 10.1016/j.vaccine.2011.03.022

Giri, P.K., and Schorey, J.S. (2008). Exosomes derived from M. Bovis BCG infected macrophages activate antigen-specific CD4+ and CD8+ T cells in vitro and in vivo. PLoS ONE, 3.

Ramachandra, 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, 10.1128/IAI.01089-09

Asano, 2011, CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens, Immunity, 34, 85, 10.1016/j.immuni.2010.12.011

Cheng, 2013, Exosomes carrying mycobacterial antigens can protect mice against Mycobacterium tuberculosis infection, Eur. J. Immunol., 43, 3279, 10.1002/eji.201343727

Schorey, 2016, Extracellular vesicles and infectious diseases: New complexity to an old story, J. Clin. Investig., 126, 1181, 10.1172/JCI81132

Mallegol, 2003, Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice, Gut, 52, 1690, 10.1136/gut.52.12.1690

Mallegol, 2007, T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells, Gastroenterology, 132, 1866, 10.1053/j.gastro.2007.02.043

Buning, 2008, Multivesicular bodies in intestinal epithelial cells: Responsible for MHC class II-restricted antigen processing and origin of exosomes, Immunology, 125, 510, 10.1111/j.1365-2567.2008.02864.x

Monleon, 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, 10.4049/jimmunol.167.12.6736

Alonso, 2005, Diacylglycerol kinase alpha regulates the secretion of lethal exosomes bearing Fas ligand during activation-induced cell death of T lymphocytes, J. Biol. Chem., 280, 28439, 10.1074/jbc.M501112200

Busch, 2008, Transfer of T cell surface molecules to dendritic cells upon CD4+ T cell priming involves two distinct mechanisms, J. Immunol., 181, 3965, 10.4049/jimmunol.181.6.3965

Sugimoto, 2016, Resolution of Inflammation: What Controls Its Onset?, Front. Immunol., 7, 160, 10.3389/fimmu.2016.00160

Scrivo, 2011, Inflammation as “common soil” of the multifactorial diseases, Autoimmun. Rev., 10, 369, 10.1016/j.autrev.2010.12.006

Console, 2019, Exosomes in inflammation and role as biomarkers, Clin. Chim. Acta, 488, 165, 10.1016/j.cca.2018.11.009

Colotta, 2009, Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability, Carcinogenesis, 30, 1073, 10.1093/carcin/bgp127

Grivennikov, 2010, Immunity, inflammation, and cancer, Cell, 140, 883, 10.1016/j.cell.2010.01.025

Wu, 2016, Exosomes derived from gastric cancer cells activate NF-kappaB pathway in macrophages to promote cancer progression, Tumour Biol., 37, 12169, 10.1007/s13277-016-5071-5

Chow, 2014, Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB, Sci. Rep., 4, 5750, 10.1038/srep05750

Fabbri, 2012, MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response, Proc. Natl. Acad. Sci. USA, 109, E2110, 10.1073/pnas.1209414109

Abusamra, 2005, Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis, Blood. Cells Mol. Dis., 35, 169, 10.1016/j.bcmd.2005.07.001

Ye, 2014, Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma, Oncotarget, 5, 5439, 10.18632/oncotarget.2118

Dagenais, 2013, Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease, Inflamm. Bowel. Dis., 19, 2227, 10.1097/MIB.0b013e31828dcac7

Mitsuhashi, 2016, Luminal Extracellular Vesicles (EVs) in Inflammatory Bowel Disease (IBD) Exhibit Proinflammatory Effects on Epithelial Cells and Macrophages, Inflamm. Bowel. Dis., 22, 1587, 10.1097/MIB.0000000000000840

Lv, 2018, Exosomal CCL2 from Tubular Epithelial Cells Is Critical for Albumin-Induced Tubulointerstitial Inflammation, J. Am. Soc. Nephrol., 29, 919, 10.1681/ASN.2017050523

Deng, 2009, Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance, Diabetes, 58, 2498, 10.2337/db09-0216

Ferrante, 2015, Adipocyte-derived exosomal miRNAs: A novel mechanism for obesity-related disease, Pediatr. Res., 77, 447, 10.1038/pr.2014.202

Kato, 2014, Exosomes from IL-1beta stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes, Arthritis Res. Ther., 16, R163, 10.1186/ar4679

Li, 2018, Microglia and macrophages in brain homeostasis and disease, Nat. Rev. Immunol., 18, 225, 10.1038/nri.2017.125

Gupta, 2014, Exosomes as mediators of neuroinflammation, J. Neuroinflamm., 11, 68, 10.1186/1742-2094-11-68

Logozzi, M., De Milito, A., Lugini, L., Borghi, M., Calabro, L., Spada, M., Perdicchio, M., Marino, M.L., Federici, C., and Iessi, E. (2009). High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE, 4.

Welker, M.W., Reichert, D., Susser, S., Sarrazin, C., Martinez, Y., Herrmann, E., Zeuzem, S., Piiper, A., and Kronenberger, B. (2012). Soluble serum CD81 is elevated in patients with chronic hepatitis C and correlates with alanine aminotransferase serum activity. PLoS ONE, 7.

Skog, 2008, Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers, Nat. Cell Biol., 10, 1470, 10.1038/ncb1800

Rajendran, 2006, Alzheimer’s disease beta-amyloid peptides are released in association with exosomes, Proc. Natl. Acad. Sci. USA, 103, 11172, 10.1073/pnas.0603838103

Saman, 2012, Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease, J. Biol. Chem., 287, 3842, 10.1074/jbc.M111.277061

Goetzl, 2015, Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease, Neurology, 85, 40, 10.1212/WNL.0000000000001702

Zhou, 2008, Urinary exosomal transcription factors, a new class of biomarkers for renal disease, Kidney Int., 74, 613, 10.1038/ki.2008.206

Smalley, 2008, Isolation and identification of potential urinary microparticle biomarkers of bladder cancer, J. Proteome Res., 7, 2088, 10.1021/pr700775x

Melo, 2015, Glypican-1 identifies cancer exosomes and detects early pancreatic cancer, Nature, 523, 177, 10.1038/nature14581

Chen, 2012, Secreted microRNAs: A new form of intercellular communication, Trends Cell Biol., 22, 125, 10.1016/j.tcb.2011.12.001

Calin, 2002, Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia, Proc. Natl. Acad. Sci. USA, 99, 15524, 10.1073/pnas.242606799

Taylor, 2008, MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer, Gynecol. Oncol., 110, 13, 10.1016/j.ygyno.2008.04.033

Rabinowits, 2009, Exosomal microRNA: A diagnostic marker for lung cancer, Clin. Lung. Cancer, 10, 42, 10.3816/CLC.2009.n.006

Silva, 2011, Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival, Eur. Respir. J., 37, 617, 10.1183/09031936.00029610

Mitchell, 2008, Circulating microRNAs as stable blood-based markers for cancer detection, Proc. Natl. Acad. Sci. USA, 105, 10513, 10.1073/pnas.0804549105

Lau, 2013, Role of pancreatic cancer-derived exosomes in salivary biomarker development, J. Biol. Chem., 288, 26888, 10.1074/jbc.M113.452458

Keller, 2007, CD24 is a marker of exosomes secreted into urine and amniotic fluid, Kidney Int., 72, 1095, 10.1038/sj.ki.5002486

Shi, 2015, Potential involvement of miR-375 in the premalignant progression of oral squamous cell carcinoma mediated via transcription factor KLF5, Oncotarget, 6, 40172, 10.18632/oncotarget.5502

Matsumoto, 2013, Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction, Circ. Res., 113, 322, 10.1161/CIRCRESAHA.113.301209

Li, 2016, Exosomes-Derived MiR-302b Suppresses Lung Cancer Cell Proliferation and Migration via TGFbetaRII Inhibition, Cell. Physiol. Biochem., 38, 1715, 10.1159/000443111

Cazzoli, 2013, microRNAs derived from circulating exosomes as noninvasive biomarkers for screening and diagnosing lung cancer, J. Thorac. Oncol., 8, 1156, 10.1097/JTO.0b013e318299ac32

Thind, 2016, Exosomal miRNAs as cancer biomarkers and therapeutic targets, J. Extracell. Vesicles, 5, 31292, 10.3402/jev.v5.31292

Conner, 2003, Regulated portals of entry into the cell, Nature, 422, 37, 10.1038/nature01451

Grapp, 2013, Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma, Nat. Commun., 4, 2123, 10.1038/ncomms3123

Feng, 2010, Cellular Internalization of Exosomes Occurs Through Phagocytosis, Traffic, 11, 675, 10.1111/j.1600-0854.2010.01041.x

Svensson, 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, 10.1074/jbc.M112.445403

Tian, 2014, Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery, J. Biol. Chem., 289, 22258, 10.1074/jbc.M114.588046

Nakase, 2015, Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes, Sci. Rep., 5, 10300, 10.1038/srep10300

Huang, 2015, Exosomal transfer of vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells, Int. J. Biol. Sci., 11, 961, 10.7150/ijbs.11943

Zhang, 2017, Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons, Mol. Neurobiol., 54, 2659, 10.1007/s12035-016-9851-0

Parolini, 2009, Microenvironmental pH is a key factor for exosome traffic in tumor cells, J. Biol. Chem., 284, 34211, 10.1074/jbc.M109.041152

Chivet, 2014, Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons, J. Extracell. Vesicles, 3, 24722, 10.3402/jev.v3.24722

Montecalvo, 2012, Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes, Blood, 119, 756, 10.1182/blood-2011-02-338004

Banizs, A.B., Huang, T., Nakamoto, R.K., Shi, W., and He, J. (2018). Endocytosis Pathways of Endothelial Cell Derived Exosomes. Mol. Pharm.

Maia, 2018, Exosome-Based Cell-Cell Communication in the Tumor Microenvironment, Front. Cell Dev. Biol., 6, 18, 10.3389/fcell.2018.00018

Wysoczynski, 2005, Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer, Int. J. Cancer, 113, 752, 10.1002/ijc.20657

Falanga, 2003, Clotting mechanisms and cancer: Implications in thrombus formation and tumor progression, Clin. Adv. Hematol. Oncol., 1, 673

Raimondo, 2015, Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism, Cell Commun. Signal., 13, 8, 10.1186/s12964-015-0086-x

Qu, 2009, Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation, Dig. Liver Dis., 41, 875, 10.1016/j.dld.2009.04.006

Pan, 2017, Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression, J. Cancer Res. Clin. Oncol., 143, 991, 10.1007/s00432-017-2361-2

Yang, 2013, Bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro, Mol. Med. Rep., 8, 1272, 10.3892/mmr.2013.1634

Matsumoto, 2017, Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells, Cancer Sci., 108, 1803, 10.1111/cas.13310

Ramteke, 2015, Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules, Mol. Carcinog., 54, 554, 10.1002/mc.22124

Gutkin, 2016, Tumor cells derived exosomes contain hTERT mRNA and transform nonmalignant fibroblasts into telomerase positive cells, Oncotarget, 7, 59173, 10.18632/oncotarget.10384

Takasugi, 2017, Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2, Nat. Commun., 8, 15729, 10.1038/ncomms15728

Zhao, 2016, Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism, eLife, 5, e10250, 10.7554/eLife.10250

Huang, 2017, Exosomes Derived from Hypoxic Colorectal Cancer Cells Promote Angiogenesis Through Wnt4-Induced beta-Catenin Signaling in Endothelial Cells, Oncol. Res., 25, 651, 10.3727/096504016X14752792816791

Rashed, H.M., Bayraktar, E., KHelal, G., Abd-Ellah, M., Amero, P., Chavez-Reyes, A., and Rodriguez-Aguayo, C. (2017). Exosomes: From Garbage Bins to Promising Therapeutic Targets. Int. J. Mol. Sci., 18.

Narayanan, 2016, Hijacking the Cellular Mail: Exosome Mediated Differentiation of Mesenchymal Stem Cells, Stem Cells Int., 2016, 3808674, 10.1155/2016/3808674

Ismail, 2013, Macrophage microvesicles induce macrophage differentiation and miR-223 transfer, Blood, 121, 984, 10.1182/blood-2011-08-374793

Ekström, K., Omar, O., Granéli, C., Wang, X., Vazirisani, F., and Thomsen, P. (2013). Monocyte Exosomes Stimulate the Osteogenic Gene Expression of Mesenchymal Stem Cells. PLoS ONE, 8.

Gutzeit, 2014, Exosomes derived from Burkitt’s lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells, J. Immunol., 192, 5852, 10.4049/jimmunol.1302068

Solberg, 2015, Tartrate-resistant acid phosphatase (TRAP) co-localizes with receptor activator of NF-KB ligand (RANKL) and osteoprotegerin (OPG) in lysosomal-associated membrane protein 1 (LAMP1)-positive vesicles in rat osteoblasts and osteocytes, Histochem. Cell Biol., 143, 195, 10.1007/s00418-014-1272-4

Huynh, 2016, Characterization of Regulatory Extracellular Vesicles from Osteoclasts, J. Dent. Res., 95, 673, 10.1177/0022034516633189

Cui, 2016, Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression, FEBS Lett., 590, 185, 10.1002/1873-3468.12024

Wang, X., Omar, O., Vazirisani, F., Thomsen, P., and Ekstrom, K. (2018). Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLoS ONE, 13.

Liao, 2017, Hematopoietic stem cell-derived exosomes promote hematopoietic differentiation of mouse embryonic stem cells in vitro via inhibiting the miR126/Notch1 pathway, Acta Pharmacol. Sin., 39, 552, 10.1038/aps.2017.130

Goulet, C.R., Champagne, A., Bernard, G., Vandal, D., Chabaud, S., Pouliot, F., and Bolduc, S. (2019). Cancer-associated fibroblasts induce epithelial–mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer, 19.

Xu, 2019, Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-beta, Cytotechnology, 71, 57, 10.1007/s10616-018-0264-y

Willis, 2017, Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency, Front. Cardiovasc. Med., 4, 63, 10.3389/fcvm.2017.00063

Teng, 2015, Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation, Cell. Physiol. Biochem., 37, 2415, 10.1159/000438594

Lou, 2017, Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases, Exp. Mol. Med., 49, e346, 10.1038/emm.2017.63

Lee, 2012, Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension, Circulation, 126, 2601, 10.1161/CIRCULATIONAHA.112.114173

Xin, 2013, Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats, J. Cereb. Blood Flow Metab., 33, 1711, 10.1038/jcbfm.2013.152

Yu, 2015, Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection, Int. J. Cardiol., 182, 349, 10.1016/j.ijcard.2014.12.043

Wang, 2015, Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium, Int. J. Cardiol., 192, 61, 10.1016/j.ijcard.2015.05.020

Khan, 2015, Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction, Circ. Res., 117, 52, 10.1161/CIRCRESAHA.117.305990

Vrijsen, 2016, Exosomes from Cardiomyocyte Progenitor Cells and Mesenchymal Stem Cells Stimulate Angiogenesis Via EMMPRIN, Adv. Healthc. Mater., 5, 2555, 10.1002/adhm.201600308

Baglio, 2013, MicroRNA expression profiling of human bone marrow mesenchymal stem cells during osteogenic differentiation reveals Osterix regulation by miR-31, Gene, 527, 321, 10.1016/j.gene.2013.06.021

Arntz, 2015, Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models, Mol. Nutr. Food Res., 59, 1701, 10.1002/mnfr.201500222

Andre, 2004, 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., 172, 2126, 10.4049/jimmunol.172.4.2126

Morishita, 2016, Exosome-based tumor antigens-adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA, Biomaterials, 111, 55, 10.1016/j.biomaterials.2016.09.031

Morishita, 2017, Enhanced Class I Tumor Antigen Presentation via Cytosolic Delivery of Exosomal Cargos by Tumor-Cell-Derived Exosomes Displaying a pH-Sensitive Fusogenic Peptide, Mol. Pharm., 14, 4079, 10.1021/acs.molpharmaceut.7b00760

Doeppner, 2015, Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression, Stem Cells Transl. Med., 4, 1131, 10.5966/sctm.2015-0078

Bruno, 2009, Mesenchymal stem cell-derived microvesicles protect against acute tubular injury, J. Am. Soc. Nephrol., 20, 1053, 10.1681/ASN.2008070798

Li, 2013, Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis, Stem Cells Dev., 22, 845, 10.1089/scd.2012.0395

Lamparski, 2002, Production and characterization of clinical grade exosomes derived from dendritic cells, J. Immunol. Methods, 270, 211, 10.1016/S0022-1759(02)00330-7

Mittelbrunn, 2013, Transfer of extracellular vesicles during immune cell-cell interactions, Immunol. Rev., 251, 125, 10.1111/imr.12013

Hadla, 2016, Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models, Nanomedicine, 11, 2431, 10.2217/nnm-2016-0154

Kim, 2016, Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells, Nanomedicine, 12, 655, 10.1016/j.nano.2015.10.012

Lou, 2015, Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma, J. Hematol. Oncol., 8, 122, 10.1186/s13045-015-0220-7

Katakowski, 2013, Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth, Cancer Lett., 335, 201, 10.1016/j.canlet.2013.02.019

Shtam, 2013, Exosomes are natural carriers of exogenous siRNA to human cells in vitro, Cell Commun. Signal., 11, 88, 10.1186/1478-811X-11-88

Jiang, 2016, Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats, Stem Cell Res. Ther., 7, 24, 10.1186/s13287-016-0287-2

Venkat, 2017, White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies, Neurobiol. Aging, 50, 96, 10.1016/j.neurobiolaging.2016.11.002

Nakano, 2016, Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes, Sci. Rep., 6, 24805, 10.1038/srep24805

Arslan, 2013, Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury, Stem Cell Res., 10, 301, 10.1016/j.scr.2013.01.002

Chen, 2013, Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury, Biochem. Biophys. Res. Commun., 431, 566, 10.1016/j.bbrc.2013.01.015

Munagala, 2016, Bovine milk-derived exosomes for drug delivery, Cancer Lett., 371, 48, 10.1016/j.canlet.2015.10.020

Sun, 2010, A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes, Mol. Ther., 18, 1606, 10.1038/mt.2010.105

Yamashita, 2018, Possibility of Exosome-Based Therapeutics and Challenges in Production of Exosomes Eligible for Therapeutic Application, Biol. Pharm. Bull., 41, 835, 10.1248/bpb.b18-00133

Yamashita, 2016, Effect of exosome isolation methods on physicochemical properties of exosomes and clearance of exosomes from the blood circulation, Eur. J. Pharm. Biopharm., 98, 1, 10.1016/j.ejpb.2015.10.017

Charoenviriyakul, 2017, Cell type-specific and common characteristics of exosomes derived from mouse cell lines: Yield, physicochemical properties, and pharmacokinetics, Eur. J. Pharm. Sci., 96, 316, 10.1016/j.ejps.2016.10.009

Ramirez, 2018, Technical challenges of working with extracellular vesicles, Nanoscale, 10, 881, 10.1039/C7NR08360B

Watson, 2016, Efficient production and enhanced tumor delivery of engineered extracellular vesicles, Biomaterials, 105, 195, 10.1016/j.biomaterials.2016.07.003

Harmati, 2017, Stressors alter intercellular communication and exosome profile of nasopharyngeal carcinoma cells, J. Oral Pathol. Med., 46, 259, 10.1111/jop.12486

Bobrie, A., Colombo, M., Krumeich, S., Raposo, G., and Thery, C. (2012). Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J. Extracell. Vesicles, 1.

Lesniak, 2012, Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells, ACS Nano, 6, 5845, 10.1021/nn300223w

Willms, 2016, Cells release subpopulations of exosomes with distinct molecular and biological properties, Sci. Rep., 6, 22519, 10.1038/srep22519

Kowal, 2016, Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes, Proc. Natl. Acad. Sci. USA, 113, E968, 10.1073/pnas.1521230113

Bosch, 2016, Trehalose prevents aggregation of exosomes and cryodamage, Sci. Rep., 6, 36162, 10.1038/srep36162

Lamichhane, 2017, Ethanol Induces Enhanced Vascularization Bioactivity of Endothelial Cell-Derived Extracellular Vesicles via Regulation of MicroRNAs and Long Non-Coding RNAs, Sci. Rep., 7, 13794, 10.1038/s41598-017-14356-2

Cui, 2018, Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice, FASEB J., 32, 654, 10.1096/fj.201700600R