Extracellular Vesicles: Overview and Clinical Implications

Abstract The release of extracellular vesicles (EVs) is a phenomenon shared by all cell types as a means of communication. Characterization and classification of EVs is challenging and still a matter of debate. However, a general consensus on EVs nomenclatura has been made, on the basis of their size, formation and release mechanisms. EVs has been classified into exosomes, secreted via exocytosis from the late endosome multivesicular bodies, whereas microvesicles (MVs) bud from the plasma membrane and apoptotic bodies are released by cells undergoing apoptosis. Initially regarded as cellular debris, EVs have gained considerable interest in basic sciences and medical research, both as biomarkers and mediators of biological functions. Indeed, EVs carry regulatory molecules including lipid, proteins and different RNA species through the extracellular spaces and deliver these cargos to target cells to modify cellular activity, thereby contributing to both physiological and pathological responses. Because EVs bear markers derived from their parent cells and can be detected in most body fluids, characterization of EVs of different cellular origin is an underestimated source of biological information on cellular activation during disease evolution, and will probably serve as valuable diagnostic and prognostic biomarker in the future. However, the current methods used for the EVs isolation and analysis have several limitations and lack standardization, leading to uncertainties regarding the subtypes of EVs studied and how to interpret the data. After a rapid overview of the current knowledge on the mechanisms of formation, subcellular origin and composition of the different types of EVs, this presentation will focus on microvesicles (MVs). We will first address how their structure/function diversity determines their multifaceted biological functions in coagulation, inflammation, angiogenesis and endothelial dysfunction (ref 1, 2, 3). Secondly, we will summarize the current debate on the different methodologies available for their analysis and quantification in body fluids. A specific attention will be devoted to standardization of sample processing and MVs analysis, and also to recommendations from scientific societies for EVs translational applications as emerging biomarkers measurable in liquid biopsies (ref 4, 5, 6). Finally, focusing on cardiovascular diseases and cancer as emerging field where MVs detection have promising impact to improve patient management, we will illustrate how combination of increasing fundamental knowledge, technological progress and standardization will push MVs towards reliable biomarkers ready for the clinics. 1- Ridger VC, Boulanger CM, Angelillo-Scherrer A, Badimon L, Blanc-Brude O, Bochaton-Piallat ML, Boilard E, Buzas EI, Caporali A, Dignat-George F, Evans PC, Lacroix R, Lutgens E, Ketelhuth DFJ, Nieuwland R, Toti F, Tunon J, Weber C, Hoefer IE. Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology. Thromb Haemost. 2017;28;117(7):1296-1316. 2- Todorova D, Simoncini S, Lacroix R, Sabatier F, Dignat-George F. Extracellular Vesicles in Angiogenesis. Circ Res. 2017;12;120(10):1658-1673. 3- Lacroix R, Dubois C, Leroyer AS, Sabatier F, Dignat-George F. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost. 2013;11 Suppl 1:24-35. 4- Coumans FAW, Brisson AR, Buzas EI, Dignat-George F, Drees EEE, El-Andaloussi S, Emanueli C, Gasecka A, Hendrix A, Hill AF, Lacroix R, Lee Y, van Leeuwen TG, Mackman N, Mäger I, Nolan JP, van der Pol E, Pegtel DM, Sahoo S, Siljander PRM, Sturk G, de Wever O, Nieuwland R. Methodological Guidelines to Study Extracellular Vesicles. Circ Res. 2017;12;120(10):1632-1648. 5-Lacroix R, Judicone C, Mooberry M, Boucekine M, Key NS, Dignat-George F; The ISTH SSC Workshop. Standardization of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost. 2013 Apr 2. 6- Cointe S, Judicone C, Robert S, Mooberry MJ, Poncelet P, Wauben M, Nieuwland R, Key NS, Dignat-George F, Lacroix R. Standardization of microparticle enumeration across different flow cytometry platforms: results of a multicenter collaborative workshop. J Thromb Haemost. 2017;15(1):187-193. Disclosures No relevant conflicts of interest to declare.