Extracellular vesicles: Exosomes, microvesicles, and friends

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

[1]  J. W. Jansen,et al.  Distinct lipid compositions of two types of human prostasomes , 2013, Proteomics.

[2]  E. N. Nolte-‘t Hoen,et al.  Dynamics of dendritic cell‐derived vesicles: high‐resolution flow cytometric analysis of extracellular vesicle quantity and quality , 2013, Journal of leukocyte biology.

[3]  C. Harding,et al.  Exosomes: Looking back three decades and into the future , 2013, The Journal of cell biology.

[4]  P. Thibault,et al.  Drosophila S2 Cells Secrete Wingless on Exosome‐Like Vesicles but the Wingless Gradient Forms Independently of Exosomes , 2013, Traffic.

[5]  J. Wrana,et al.  Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration , 2012, Cell.

[6]  P. Altevogt,et al.  Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation , 2012, PLoS biology.

[7]  Julia Christina Gross,et al.  Active Wnt proteins are secreted on exosomes , 2012, Nature Cell Biology.

[8]  A. Hill,et al.  Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells , 2012, Nucleic acids research.

[9]  M. Zöller,et al.  Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. , 2012, The international journal of biochemistry & cell biology.

[10]  H. Buermans,et al.  Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions , 2012, Nucleic acids research.

[11]  Ylva Ivarsson,et al.  Syndecan–syntenin–ALIX regulates the biogenesis of exosomes , 2012, Nature Cell Biology.

[12]  Willem Stoorvogel,et al.  Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry , 2012, Nature Protocols.

[13]  Elaine C. Campbell,et al.  Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells , 2012, Immunology.

[14]  J. Lötvall,et al.  Importance of RNA isolation methods for analysis of exosomal RNA: evaluation of different methods. , 2012, Molecular immunology.

[15]  W. Stoorvogel,et al.  Identification of Distinct Populations of Prostasomes That Differentially Express Prostate Stem Cell Antigen, Annexin A1, and GLIPR2 in Humans1 , 2012, Biology of reproduction.

[16]  Stanley N Cohen,et al.  Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein , 2012, Proceedings of the National Academy of Sciences.

[17]  Simon C Watkins,et al.  Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. , 2012, Blood.

[18]  A. Hupalowska,et al.  The New Faces of Endocytosis in Signaling , 2012, Traffic.

[19]  Ger J.A. Arkesteijn,et al.  Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles , 2011, Nanomedicine: Nanotechnology, Biology and Medicine.

[20]  Clotilde Théry,et al.  Exosome Secretion: Molecular Mechanisms and Roles in Immune Responses , 2011, Traffic.

[21]  S. Prusiner,et al.  Prion Uptake in the Gut: Identification of the First Uptake and Replication Sites , 2011, PLoS pathogens.

[22]  Arsen O. Batagov,et al.  Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles , 2011, BMC Genomics.

[23]  P. Saftig,et al.  The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. , 2011, Developmental cell.

[24]  Beiyi Shen,et al.  Biogenesis of the Posterior Pole Is Mediated by the Exosome/Microvesicle Protein-sorting Pathway* , 2011, The Journal of Biological Chemistry.

[25]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[26]  G. R. Hankins,et al.  Chromatin modifying protein 1A (Chmp1A) of the endosomal sorting complex required for transport (ESCRT)-III family activates ataxia telangiectasia mutated (ATM) for PanC-1 cell growth inhibition , 2011, Cell cycle.

[27]  S. Wickline,et al.  Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. , 2011, Cancer research.

[28]  F. Benfenati,et al.  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 , 2011, The Journal of Neuroscience.

[29]  Hyoung-Tae Kim,et al.  Ca2+ Signaling Tools Acquired from Prostasomes Are Required for Progesterone-Induced Sperm Motility , 2011, Science Signaling.

[30]  György Nagy,et al.  Cellular and Molecular Life Sciences REVIEW Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles , 2022 .

[31]  Fátima Sánchez-Cabo,et al.  Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells , 2011, Nature communications.

[32]  G. Lachenal,et al.  Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity , 2011, Molecular and Cellular Neuroscience.

[33]  W. Grizzle,et al.  Exosomes and Cancer: A Newly Described Pathway of Immune Suppression , 2011, Clinical Cancer Research.

[34]  Tosifusa Toda,et al.  Proteomic analysis of two types of exosomes in human whole saliva. , 2011, Biological & pharmaceutical bulletin.

[35]  Clotilde Théry,et al.  Exosomes: immune properties and potential clinical implementations , 2011, Seminars in Immunopathology.

[36]  J. Hurley The ESCRT complexes , 2010, Critical reviews in biochemistry and molecular biology.

[37]  Willem Stoorvogel,et al.  MHC class II‐associated proteins in B‐cell exosomes and potential functional implications for exosome biogenesis , 2010, Immunology and cell biology.

[38]  J. Rak Microparticles in cancer. , 2010, Seminars in thrombosis and hemostasis.

[39]  M. Simons,et al.  Inhibition of Myelin Membrane Sheath Formation by Oligodendrocyte-derived Exosome-like Vesicles* , 2010, The Journal of Biological Chemistry.

[40]  Haitao Wang,et al.  Visualizing of the cellular uptake and intracellular trafficking of exosomes by live‐cell microscopy , 2010, Journal of cellular biochemistry.

[41]  N. LaRusso,et al.  Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[42]  A. Harris,et al.  New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. , 2010, Blood.

[43]  S. Gabrielsson,et al.  Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis , 2010, Thorax.

[44]  N. Tanaka,et al.  Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. , 2010, Biochemical and biophysical research communications.

[45]  M. Ntzouni,et al.  Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival , 2010, The Journal of Neuroscience.

[46]  Crislyn D'Souza-Schorey,et al.  Microvesicles: mediators of extracellular communication during cancer progression , 2010, Journal of Cell Science.

[47]  W. Möbius,et al.  Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C , 2010, The Journal of cell biology.

[48]  M. Vidal,et al.  Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. , 2010, Blood.

[49]  G. Illei,et al.  Exosomes from human saliva as a source of microRNA biomarkers. , 2010, Oral diseases.

[50]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.

[51]  M. B. Mestre,et al.  TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. , 2009, Biochimica et biophysica acta.

[52]  Graca Raposo,et al.  ARF6-Regulated Shedding of Tumor Cell-Derived Plasma Membrane Microvesicles , 2009, Current Biology.

[53]  C. Melief,et al.  MHC II in Dendritic Cells is Targeted to Lysosomes or T Cell‐Induced Exosomes Via Distinct Multivesicular Body Pathways , 2009, Traffic.

[54]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[55]  Graça Raposo,et al.  Exosomes--vesicular carriers for intercellular communication. , 2009, Current opinion in cell biology.

[56]  J. Rak,et al.  Microvesicles: Messengers and mediators of tumor progression , 2009, Cell cycle.

[57]  A. Brech,et al.  Multivesicular Endosome Biogenesis in the Absence of ESCRTs , 2009, Traffic.

[58]  Robert L Moritz,et al.  Exosomes: proteomic insights and diagnostic potential , 2009, Expert review of proteomics.

[59]  Harald Stenmark,et al.  The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins , 2009, Nature.

[60]  H. Korswagen,et al.  Mammalian Wnt3a is Released on Lipoprotein Particles , 2009, Traffic.

[61]  T. Niki,et al.  Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. , 2009, Blood.

[62]  Willem Stoorvogel,et al.  Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. , 2009, Blood.

[63]  Jacopo Meldolesi,et al.  Shedding microvesicles: artefacts no more. , 2009, Trends in cell biology.

[64]  Douglas D. Taylor,et al.  Exosomal microRNA: a diagnostic marker for lung cancer. , 2008, Clinical lung cancer.

[65]  M. Zöller Tetraspanins: push and pull in suppressing and promoting metastasis , 2009, Nature Reviews Cancer.

[66]  Qinxi Li,et al.  Axin determines cell fate by controlling the p53 activation threshold after DNA damage , 2009, Nature Cell Biology.

[67]  Miguel C. Seabra,et al.  1 Rab 27 a and Rab 27 b control different steps of the exosome secretion pathway , 2009 .

[68]  Rune Matthiesen,et al.  Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. , 2008, Journal of proteome research.

[69]  Lianbo Yu,et al.  Detection of microRNA Expression in Human Peripheral Blood Microvesicles , 2008, PloS one.

[70]  L. R. Padial,et al.  Recent advances in atherosclerosis-based proteomics: new biomarkers and a future perspective , 2008, Expert review of proteomics.

[71]  D. Skupski,et al.  Heat shock protein-containing exosomes in mid-trimester amniotic fluids. , 2008, Journal of reproductive immunology.

[72]  M. Hemler Targeting of tetraspanin proteins — potential benefits and strategies , 2008, Nature Reviews Drug Discovery.

[73]  C. Théry,et al.  Exosomes from Bronchoalveolar Fluid of Tolerized Mice Prevent Allergic Reaction1 , 2008, The Journal of Immunology.

[74]  M. Futai,et al.  The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function , 2008, Current Opinion in Cell Biology.

[75]  Petra Schwille,et al.  Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes , 2008, Science.

[76]  P. Altevogt,et al.  Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis , 2007, Neuroscience Letters.

[77]  S. Tenzer,et al.  Oligodendrocytes secrete exosomes containing major myelin and stress‐protective proteins: Trophic support for axons? , 2007, Proteomics. Clinical applications.

[78]  Luigi Biancone,et al.  Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. , 2007, Blood.

[79]  G. Raposo,et al.  Lysosome-related organelles: driving post-Golgi compartments into specialisation. , 2007, Current opinion in cell biology.

[80]  N. Hogg,et al.  CD8+ Dendritic Cells Use LFA-1 to Capture MHC-Peptide Complexes from Exosomes In Vivo1 , 2007, The Journal of Immunology.

[81]  Riitta Lahesmaa,et al.  Exosomes with Immune Modulatory Features Are Present in Human Breast Milk1 , 2007, The Journal of Immunology.

[82]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[83]  H. Cai,et al.  Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. , 2007, Developmental cell.

[84]  T. Galli,et al.  Expression of the Longin domain of TI‐VAMP impairs lysosomal secretion and epithelial cell migration , 2007, Biology of the cell.

[85]  G. Raposo,et al.  T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. , 2007, Gastroenterology.

[86]  R. Cappai,et al.  Packaging of prions into exosomes is associated with a novel pathway of PrP processing , 2007, The Journal of pathology.

[87]  M. Record,et al.  Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. , 2007, Biochimie.

[88]  D. Johnston,et al.  bicoid RNA localization requires specific binding of an endosomal sorting complex , 2007, Nature.

[89]  B. Rothen‐Rutishauser,et al.  Exovesicles from human activated dendritic cells fuse with resting dendritic cells, allowing them to present alloantigens. , 2006, The American journal of pathology.

[90]  J Ratajczak,et al.  Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication , 2006, Leukemia.

[91]  P. Verkade,et al.  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[92]  G. Raposo,et al.  Exosomes: a common pathway for a specialized function. , 2006, Journal of biochemistry.

[93]  M. Labouesse,et al.  The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans , 2006, The Journal of cell biology.

[94]  A. Levine,et al.  The regulation of exosome secretion: a novel function of the p53 protein. , 2006, Cancer research.

[95]  G. Lachenal,et al.  Exosomes are released by cultured cortical neurones , 2006, Molecular and Cellular Neuroscience.

[96]  A. Booth,et al.  Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane , 2006, The Journal of cell biology.

[97]  G. Raposo,et al.  A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. , 2006, Developmental cell.

[98]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[99]  S. Eaton Release and trafficking of lipid-linked morphogens. , 2006, Current opinion in genetics & development.

[100]  A. Morelli The Immune Regulatory Effect of Apoptotic Cells and Exosomes on Dendritic Cells: Its Impact on Transplantation , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[101]  C. Futter,et al.  EGF stimulates annexin 1‐dependent inward vesiculation in a multivesicular endosome subpopulation , 2006, The EMBO journal.

[102]  Graça Raposo,et al.  Exosomal-like vesicles are present in human blood plasma. , 2005, International immunology.

[103]  Suzanne Eaton,et al.  Lipoprotein particles are required for Hedgehog and Wingless signalling , 2005, Nature.

[104]  M. T. Damiani,et al.  Rab11 Promotes Docking and Fusion of Multivesicular Bodies in a Calcium‐Dependent Manner , 2005, Traffic.

[105]  M. Hristov,et al.  Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. , 2004, Blood.

[106]  Rong-Fong Shen,et al.  Identification and proteomic profiling of exosomes in human urine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[107]  D. Crossman,et al.  Secretion of Intracellular IL-1 Receptor Antagonist (Type 1) Is Dependent on P2X7 Receptor Activation1 , 2004, The Journal of Immunology.

[108]  W. Faigle,et al.  Cells release prions in association with exosomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[109]  Sébastien Roy,et al.  Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. , 2004, The Biochemical journal.

[110]  C. Huynh,et al.  Identification of SNAREs Involved in Synaptotagmin VII-regulated Lysosomal Exocytosis* , 2004, Journal of Biological Chemistry.

[111]  M. Vidal,et al.  Degradation of AP2 During Reticulocyte Maturation Enhances Binding of Hsc70 and Alix to a Common Site on TfR for Sorting into Exosomes , 2004, Traffic.

[112]  G. Ronquist,et al.  Promotive effect on human sperm progressive motility by prostasomes , 2004, Urological Research.

[113]  M. Hemler Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. , 2003, Annual review of cell and developmental biology.

[114]  E. Tomaskovic-Crook,et al.  Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice , 2003, Gut.

[115]  J. Slot,et al.  Proteomic and Biochemical Analyses of Human B Cell-derived Exosomes , 2003, The Journal of Biological Chemistry.

[116]  L. Zitvogel,et al.  Malignant effusions and immunogenic tumour-derived exosomes , 2002, The Lancet.

[117]  M. Vidal,et al.  The exosome pathway in K562 cells is regulated by Rab11. , 2002, Journal of cell science.

[118]  A. Régnault,et al.  TCR Activation of Human T Cells Induces the Production of Exosomes Bearing the TCR/CD3/ζ Complex1 , 2002, The Journal of Immunology.

[119]  J. Slot,et al.  Immunoelectron Microscopic Localization of Cholesterol Using Biotinylated and Non-cytolytic Perfringolysin O , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[120]  G. Raposo,et al.  Intestinal epithelial cells secrete exosome-like vesicles. , 2001, Gastroenterology.

[121]  P. Ricciardi-Castagnoli,et al.  Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles1 , 2001, The Journal of Immunology.

[122]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[123]  M. Kleijmeer,et al.  Follicular Dendritic Cells Carry MHC Class II-Expressing Microvesicles at Their Surface1 , 2000, The Journal of Immunology.

[124]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[125]  P. Ricciardi-Castagnoli,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[126]  C. Hess,et al.  Ectosomes released by human neutrophils are specialized functional units. , 1998, Journal of immunology.

[127]  J J Sixma,et al.  Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. , 1999, Blood.

[128]  H. Geuze,et al.  Selective Enrichment of Tetraspan Proteins on the Internal Vesicles of Multivesicular Endosomes and on Exosomes Secreted by Human B-lymphocytes* , 1998, The Journal of Biological Chemistry.

[129]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[130]  N. Debili,et al.  Multivesicular Bodies Are an Intermediate Stage in the Formation of Platelet α-Granules , 1998 .

[131]  N. Debili,et al.  Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules. , 1998, Blood.

[132]  G. Raposo,et al.  Accumulation of Major Histocompatibility Complex Class Ii Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation Generation of Bmmcs Preparation of B Cells Reagents and Monoclonal Antibodies (mabs) Immunofluorescence Staining and Confocal Microscopy Pulse-chase# Labeling and , 2022 .

[133]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[134]  M. Abdelnoor,et al.  Demonstration of Platelet-Derived Microvesicles in Blood from Patients with Activated Coagulation and Fibrinolysis Using a Filtration Technique and Western Blotting , 1994, Thrombosis and Haemostasis.

[135]  I. Brody,et al.  The prostasome: its secretion and function in man. , 1985, Biochimica et biophysica acta.

[136]  M. Adam,et al.  Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes , 1985, The Journal of cell biology.

[137]  C. Harding,et al.  Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. , 1984, European journal of cell biology.

[138]  E. Trams,et al.  Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. , 1981, Biochimica et biophysica acta.