Extracellular Vesicles: Unique Intercellular Delivery Vehicles.

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargoes including proteins, lipids, and nucleic acids. While the release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells. This review focuses on recent findings and knowledge gaps in the area of EV biogenesis, release, and uptake. In addition, we highlight examples whereby EV cargoes control basic cellular functions, including motility and polarization, immune responses, and development, and contribute to diseases such as cancer and neurodegeneration.

[1]  T. Okada,et al.  Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes , 2013, Nature Communications.

[2]  B. W. van Balkom,et al.  Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting , 2015, Journal of extracellular vesicles.

[3]  Jedd D. Wolchok,et al.  PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations , 2016, Science Translational Medicine.

[4]  F. Court,et al.  Schwann cell‐derived exosomes enhance axonal regeneration in the peripheral nervous system , 2013, Glia.

[5]  K. Törrönen,et al.  Hyaluronan production enhances shedding of plasma membrane-derived microvesicles. , 2013, Experimental cell research.

[6]  David L. Tabb,et al.  The enterocyte microvillus is a vesicle-generating organelle , 2009, The Journal of cell biology.

[7]  Lesley Cheng,et al.  Focus on Extracellular Vesicles: Exosomes and Their Role in Protein Trafficking and Biomarker Potential in Alzheimer’s and Parkinson’s Disease , 2016, International journal of molecular sciences.

[8]  Shiladitya Sengupta,et al.  Physical nanoscale conduit-mediated communication between tumour cells and the endothelium modulates endothelial phenotype , 2015, Nature Communications.

[9]  Aiman S Saab,et al.  Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication , 2013, PLoS biology.

[10]  J. van Rheenen,et al.  Implications of Extracellular Vesicle Transfer on Cellular Heterogeneity in Cancer: What Are the Potential Clinical Ramifications? , 2016, Cancer research.

[11]  W. Huttner,et al.  Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin-1 , 2007, The Journal of cell biology.

[12]  Martin Hintersteiner,et al.  The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing , 2013, The EMBO journal.

[13]  N. Copeland,et al.  A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  E. Clementi,et al.  Acid sphingomyelinase activity triggers microparticle release from glial cells , 2009 .

[15]  David L. Stokes,et al.  Polarized release of TCR-enriched microvesicles at the T cell immunological synapse , 2014, Nature.

[16]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[17]  James W. Clancy,et al.  Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion , 2015, Scientific Reports.

[18]  Melissa M. Sprachman,et al.  SCS macrophages suppress melanoma by restricting tumor-derived vesicle–B cell interactions , 2016, Science.

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

[20]  M. Barr,et al.  Ciliary Extracellular Vesicles: Txt Msg Organelles , 2016, Cellular and Molecular Neurobiology.

[21]  C. Théry,et al.  Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes , 2016, Proceedings of the National Academy of Sciences.

[22]  G. Raposo,et al.  Vertebrate Hedgehog is secreted on two types of extracellular vesicles with different signaling properties , 2014, Scientific Reports.

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

[24]  Jun Yao,et al.  Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth , 2015, Nature.

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

[26]  L. O’Driscoll,et al.  Biological properties of extracellular vesicles and their physiological functions , 2015, Journal of extracellular vesicles.

[27]  C. Théry,et al.  Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. , 2014, Annual review of cell and developmental biology.

[28]  M. Rubin,et al.  Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. , 2012, The American journal of pathology.

[29]  Alissa M. Weaver,et al.  Directional cell movement through tissues is controlled by exosome secretion , 2015, Nature Communications.

[30]  M. Zöller,et al.  Host matrix modulation by tumor exosomes promotes motility and invasiveness. , 2013, Neoplasia.

[31]  Clotilde Théry,et al.  Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles , 2013, Journal of Cell Science.

[32]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[33]  Jacco van Rheenen,et al.  In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior , 2015, Cell.

[34]  R. J. Kelleher,et al.  Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade , 2015, Cancer Immunology Research.

[35]  Christopher R. Wood,et al.  The Cilium Secretes Bioactive Ectosomes , 2013, Current Biology.

[36]  F. Hamdy,et al.  BMP-regulated exosomes from Drosophila male reproductive glands reprogram female behavior , 2014, The Journal of cell biology.

[37]  C. Naus,et al.  Gap junctions modulate glioma invasion by direct transfer of microRNA , 2015, Oncotarget.

[38]  Cynthia A. Reinhart-King,et al.  Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation , 2016, Nature Communications.

[39]  S. Lim,et al.  MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA , 2016, Journal of extracellular vesicles.

[40]  M. Tammi,et al.  Hyaluronan-coated extracellular vesicles--a novel link between hyaluronan and cancer. , 2014, Advances in cancer research.

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

[42]  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.

[43]  R. Klein,et al.  Exosomes mediate cell contact – independent ephrin-Eph signaling during axon guidance , 2022 .

[44]  C. Parent,et al.  Exosomes Mediate LTB4 Release during Neutrophil Chemotaxis , 2016, PLoS biology.

[45]  D. Krainc,et al.  ATP13A2/PARK9 Regulates Secretion of Exosomes and α-Synuclein , 2014, The Journal of Neuroscience.

[46]  S. Eaton,et al.  Argosomes A Potential Vehicle for the Spread of Morphogens through Epithelia , 2001, Cell.

[47]  Clotilde Théry,et al.  Communication by Extracellular Vesicles: Where We Are and Where We Need to Go , 2016, Cell.

[48]  R. Kerbel,et al.  Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR , 2009, Proceedings of the National Academy of Sciences.

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

[50]  S. Rankin,et al.  A role for Rab27 in neutrophil chemotaxis and lung recruitment , 2014, BMC Cell Biology.

[51]  A. Kleijn,et al.  Glioblastoma‐derived extracellular vesicles modify the phenotype of monocytic cells , 2015, International journal of cancer.

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

[53]  Laurence Zitvogel,et al.  Extracellular vesicles: masters of intercellular communication and potential clinical interventions. , 2016, The Journal of clinical investigation.

[54]  E. Clementi,et al.  Acid sphingomyelinase activity triggers microparticle release from glial cells , 2009, The EMBO journal.

[55]  Carmen Visus,et al.  Tumor-Derived Microvesicles Promote Regulatory T Cell Expansion and Induce Apoptosis in Tumor-Reactive Activated CD8+ T Lymphocytes1 , 2009, The Journal of Immunology.

[56]  P. A. Lay,et al.  Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes. , 2014, Human molecular genetics.

[57]  H. Stenmark,et al.  Cellular Functions and Molecular Mechanisms of the ESCRT Membrane-Scission Machinery. , 2017, Trends in biochemical sciences.

[58]  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.

[59]  T. Kondo,et al.  The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice , 2008, Proceedings of the National Academy of Sciences.

[60]  W. Snell,et al.  Uni-directional ciliary membrane protein trafficking by a cytoplasmic retrograde IFT motor and ciliary ectosome shedding , 2015, eLife.

[61]  Valentina R Minciacchi,et al.  Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. , 2015, Seminars in cell & developmental biology.

[62]  Johan Skog,et al.  Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers , 2008, Nature Cell Biology.

[63]  S. Tuck Extracellular Vesicles: Budding Regulated by a Phosphatidylethanolamine Translocase , 2011, Current Biology.

[64]  Roberta Galli,et al.  MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response , 2012, Proceedings of the National Academy of Sciences.

[65]  Bulent Ataman,et al.  Trans-Synaptic Transmission of Vesicular Wnt Signals through Evi/Wntless , 2009, Cell.

[66]  Adam Frost,et al.  Structure and membrane remodeling activity of ESCRT-III helical polymers , 2015, Science.

[67]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[68]  F. Court,et al.  Schwann Cell Exosomes Mediate Neuron–Glia Communication and Enhance Axonal Regeneration , 2016, Cellular and Molecular Neurobiology.

[69]  Xuemei Chen,et al.  MicroRNAs Inhibit the Translation of Target mRNAs on the Endoplasmic Reticulum in Arabidopsis , 2013, Cell.

[70]  Peter Satir,et al.  The primary cilium at a glance , 2010, Journal of Cell Science.

[71]  Simon C Watkins,et al.  Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs , 2015, Nature Communications.

[72]  Andrew F. Hill,et al.  Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper , 2015, Journal of extracellular vesicles.

[73]  B. Ylstra,et al.  Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. , 2014, Cell reports.

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

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

[76]  J. Freyssinet,et al.  Membrane microparticles: two sides of the coin. , 2005, Physiology.

[77]  A. Winslow,et al.  Exosomal cell-to-cell transmission of alpha synuclein oligomers , 2012, Molecular Neurodegeneration.

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

[79]  J. Nance,et al.  The P4-ATPase TAT-5 Inhibits the Budding of Extracellular Vesicles in C. elegans Embryos , 2011, Current Biology.

[80]  S. Bhattacharyya,et al.  mRNA Targeting to Endoplasmic Reticulum Precedes Ago Protein Interaction and MicroRNA (miRNA)-mediated Translation Repression in Mammalian Cells* , 2015, The Journal of Biological Chemistry.

[81]  D. Hall,et al.  C. elegans Ciliated Sensory Neurons Release Extracellular Vesicles that Function in Animal Communication , 2014, Current Biology.

[82]  C. Futter,et al.  Rab27b regulates number and secretion of platelet dense granules , 2007, Proceedings of the National Academy of Sciences.

[83]  M. Komada,et al.  Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis. , 1999, Genes & development.

[84]  C. Théry,et al.  Indirect activation of naïve CD4+ T cells by dendritic cell–derived exosomes , 2002, Nature Immunology.

[85]  Alissa M. Weaver,et al.  Exosome secretion is enhanced by invadopodia and drives invasive behavior. , 2013, Cell reports.

[86]  M. Ringnér,et al.  Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development , 2013, Proceedings of the National Academy of Sciences.

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

[88]  M. Clark Flippin' lipids , 2011, Nature Immunology.

[89]  D. Hall,et al.  Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis , 2015, Molecular biology of the cell.

[90]  X. Breakefield,et al.  Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake , 2016, Cellular and Molecular Neurobiology.

[91]  Derek H. Oakley,et al.  Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. , 2016, Neuro-oncology.

[92]  W. Kuo,et al.  Emerging technologies in extracellular vesicle-based molecular diagnostics , 2014, Expert review of molecular diagnostics.

[93]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[94]  R. Pink,et al.  Routes and mechanisms of extracellular vesicle uptake , 2014, Journal of extracellular vesicles.

[95]  W. Stoffel,et al.  Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[96]  M. Babst MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. , 2011, Current opinion in cell biology.

[97]  J. Hurley,et al.  Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly , 2015, Proceedings of the National Academy of Sciences.

[98]  T. Pritts,et al.  Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion-Associated Lung Inflammation. , 2017, Annals of surgery.

[99]  E. Bieberich,et al.  Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease , 2014, Neurobiology of Aging.

[100]  Jan Gründemann,et al.  Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase , 2006, Nature Genetics.

[101]  F. Perez,et al.  ESCRT Machinery Is Required for Plasma Membrane Repair , 2014, Science.

[102]  Martin Lenz,et al.  Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation , 2015, Cell.

[103]  H. Luhmann,et al.  Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[104]  A. Brisson,et al.  High-speed centrifugation induces aggregation of extracellular vesicles , 2015, Journal of extracellular vesicles.

[105]  A. Hill,et al.  Extracellular vesicles--Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. , 2015, Seminars in cell & developmental biology.

[106]  Jung Hoon Jung,et al.  Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo , 2013, Molecular Brain.

[107]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[108]  S. Gabrielsson,et al.  Antigen-loaded exosomes alone induce Th1-type memory through a B-cell-dependent mechanism. , 2009, Blood.

[109]  Christopher R. Wood,et al.  Ciliary ectosomes: transmissions from the cell's antenna. , 2015, Trends in cell biology.

[110]  Isobel S Okoye,et al.  MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells , 2014, Immunity.

[111]  Michael A. Hollingsworth,et al.  Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver , 2015, Nature Cell Biology.

[112]  Alissa M. Weaver,et al.  Cortactin promotes exosome secretion by controlling branched actin dynamics , 2016, The Journal of cell biology.

[113]  E. Botchwey,et al.  Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD. , 2014, Blood.

[114]  M. Record,et al.  Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. , 2014, Biochimica et biophysica acta.

[115]  John W. Gilbert,et al.  Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers , 2009, Nature.

[116]  W. Wick,et al.  A malignant cellular network in gliomas: potential clinical implications. , 2016, Neuro-oncology.

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

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

[119]  C. Bishop,et al.  A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse , 2005, Nature Genetics.

[120]  C. Genoud,et al.  Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER , 2016, The Journal of cell biology.

[121]  A. Hill,et al.  The role of extracellular vesicles in neurodegenerative diseases. , 2017, Biochemical and biophysical research communications.

[122]  L. Hennighausen,et al.  Tsg101 Is Essential for Cell Growth, Proliferation, and Cell Survival of Embryonic and Adult Tissues , 2003, Molecular and Cellular Biology.

[123]  Clare Huxley,et al.  A general role for Rab27a in secretory cells. , 2003, Molecular biology of the cell.

[124]  P. Chuang,et al.  Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. , 2013, Current opinion in genetics & development.

[125]  C. Théry,et al.  ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. , 2005, Blood.

[126]  M. Corrotte,et al.  Damage control: cellular mechanisms of plasma membrane repair. , 2014, Trends in cell biology.

[127]  James W. Clancy,et al.  Regulated Delivery of Molecular Cargo to Invasive Tumor-derived Microvesicles , 2015, Nature Communications.

[128]  M. Labouesse,et al.  RAL-1 controls multivesicular body biogenesis and exosome secretion , 2015, The Journal of cell biology.

[129]  J. Leszyk,et al.  Mechanism of Evenness Interrupted (Evi)-Exosome Release at Synaptic Boutons* , 2012, The Journal of Biological Chemistry.

[130]  Ho Chul Kang,et al.  Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3 , 2016, Science.

[131]  Jeffrey W Pollard,et al.  Tumor-associated macrophages: from mechanisms to therapy. , 2014, Immunity.

[132]  G. Raposo,et al.  Extracellular vesicles shuffling intercellular messages: for good or for bad. , 2015, Current opinion in cell biology.

[133]  V. Budnik,et al.  Regulation of Postsynaptic Retrograde Signaling by Presynaptic Exosome Release , 2013, Neuron.

[134]  A. Pivoriūnas,et al.  Exosomes as a potential novel therapeutic tools against neurodegenerative diseases. , 2016, Pharmacological research.

[135]  S. Gould,et al.  Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins , 2011, Molecular biology of the cell.

[136]  W. Jiang,et al.  Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes , 2014, Oncogene.

[137]  C. Soto,et al.  The stress of prion disease , 2016, Brain Research.

[138]  P. Roche,et al.  The ins and outs of MHC class II-mediated antigen processing and presentation , 2015, Nature Reviews Immunology.

[139]  D. Goulding,et al.  Juno is the egg Izumo receptor and is essential for mammalian fertilisation , 2014, Nature.

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