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Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: from 1946 to Today

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Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: from 1946 to Today International Journal of Molecular Sciences Review Critical Review of the Evolution of Extracellular Vesicles’ Knowledge: From 1946 to Today Erica Bazzan 1,*,† , Mariaenrica Tinè 1,† , Alvise Casara 1, Davide Biondini 1, Umberto Semenzato 1 , Elisabetta Cocconcelli 1, Elisabetta Balestro 1, Marco Damin 1, Claudia Maria Radu 2,3 , Graziella Turato 1, Simonetta Baraldo 1 , Paolo Simioni 3 , Paolo Spagnolo 1 , Marina Saetta 1,‡ and Manuel G. Cosio 1,4,‡ 1 Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy; [email protected] (M.T.); [email protected] (A.C.); [email protected] (D.B.); [email protected] (U.S.); [email protected] (E.C.); [email protected] (E.B.); [email protected] (M.D.); [email protected] (G.T.); [email protected] (S.B.); [email protected] (P.S.); [email protected] (M.S.); [email protected] (M.G.C.) 2 Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy; [email protected] 3 Department of Medicine, University of Padova, 35128 Padova, Italy; [email protected] 4 Meakins-Christie Laboratories, Respiratory Division, McGill University, Montreal, QC H3A 0G4, Canada * Correspondence: [email protected]; Tel.: +39-0498213449 † These authors contributed equally to this work as first authors. ‡ These authors contributed equally to this work as senior authors. Abstract: Extracellular vesicles (EVs) are a family of particles/vesicles present in blood and body fluids, composed of phospholipid bilayers that carry a variety of molecules that can mediate cell Citation: Bazzan, E.; Tinè, M.; communication, modulating crucial cell processes such as homeostasis, induction/dampening of Casara, A.; Biondini, D.; Semenzato, inflammation, and promotion of repair. Their existence, initially suspected in 1946 and confirmed in U.; Cocconcelli, E.; Balestro, E.; 1967, spurred a sharp increase in the number of scientific publications. Paradoxically, the increasing Damin, M.; Radu, C.M.; Turato, G.; et al. Critical Review of the Evolution interest for EV content and function progressively reduced the relevance for a precise nomenclature of Extracellular Vesicles’ Knowledge: in classifying EVs, therefore leading to a confusing scientific production. The aim of this review was From 1946 to Today. Int. J. Mol. Sci. to analyze the evolution of the progress in the knowledge and definition of EVs over the years, with 2021, 22, 6417. https://doi.org/ an overview of the methodologies used for the identification of the vesicles, their cell of origin, and 10.3390/ijms22126417 the detection of their cargo. The MISEV 2018 guidelines for the proper recognition nomenclature and ways to study EVs are summarized. The review finishes with a “more questions than answers” Academic Editor: Sigrun Lange chapter, in which some of the problems we still face to fully understand the EV function and potential as a diagnostic and therapeutic tool are analyzed. Received: 10 May 2021 Accepted: 11 June 2021 Keywords: exosomes; microvesicles; multivesicular bodies; liposomes Published: 15 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Extracellular vesicles (EVs) are a family of particles released from the cell that are delimited by a lipid bilayer and cannot replicate, i.e., do not contain a functional nucleus, and can be detected in culture supernatants of different bodily fluids [1–5]. Once considered nothing else than sticky cell debris, they are now recognized as alternative mediators of cell communication, being able to convey a broad range of molecules such as cytokines, Copyright: © 2021 by the authors. inflammatory mediators, and miRNA [1–6], crucial in the maintenance of homeostasis, Licensee MDPI, Basel, Switzerland. This article is an open access article induction/dampening of inflammation, and promotion of repair [1–6]. Recognized today distributed under the terms and as “extracellular vesicles” (EVs), they were initially stratified and nominated based on conditions of the Creative Commons their size from <100 nm, traditionally named exosomes; 100 to 1000 nm, also recognized Attribution (CC BY) license (https:// as microvesicles, microparticles or ectosomes; and apoptotic bodies when >1000 nm [7], a creativecommons.org/licenses/by/ nomenclature that was eventually modified after the MISEV 18 guidelines. 4.0/). Int. J. Mol. Sci. 2021, 22, 6417. https://doi.org/10.3390/ijms22126417 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x 2 of 13 As shown by the number of publications (Figure 1), there has been an exponential increase in the interest in EVs and their potential applications in understanding the un- derlying mechanisms of various diseases, such as cancer, cardiovascular, metabolic, neu- rological, and infectious diseases, among others, which have revealed a role for EVs as promising biomarker candidates for diagnosis, prognosis, and even therapeutic tools, in lung and other diseases [8–11]. Furthermore, investigations performed with cell cultures of peripheral and epithelial cells from various systems highlight the peculiar release of specific cargoes of these particles when exposed to different triggers, which points to the Int. J. Mol. Sci. 2021, 22, 6417 possibility that EVs might be bioengineered as shuttles of therapeutic drugs, offering2 of an 13 alternative way of drug delivery for disease treatment [9,11]. Currently, the most striking evidence of their importance comes from the study of circulating human EVs in inflammatory disorders, and even more from the recognition of As shown by the number of publications (Figure1), there has been an exponential their presence in body fluids [12]. EV-containing “liquid biopsies” such as blood [13], BAL increase in the interest in EVs and their potential applications in understanding the underly- [14],ing mechanismsurine [15], saliva of various [13], diseases,and cerebrospinal such as cancer, fluid cardiovascular, [16] can be obtained metabolic, in an neurological, easy and minimallyand infectious invasive diseases, way amongand are others,seen as which a promising have revealed alternative a role to forregular EVs asbiopsies promising [9]. Indeed,biomarker the candidatescomprehensive for diagnosis, characterization prognosis, of EVs and and even of therapeutic their content tools, in body in lung fluids and mightother diseasesoffer the [key8–11 to]. better Furthermore, understand investigations disease development performed withand treatment. cell cultures of periph- eral and epithelial cells from various systems highlight the peculiar release of specific 2.cargoes Evolution of these of the particles EVs Nomenclature: when exposed toFrom different 1946 to triggers, Today which points to the possibility thatAs EVs shown might in be Figure bioengineered 1, recent asdecades shuttles have of therapeutic seen a sharp drugs, increase offering in the an number alternative of scientificway of drug publications delivery fordescribing disease treatmentthe physiological [9,11]. and pathological functions of “extra- cellularCurrently, vesicles” the (EVs), most a collective striking evidence term covering of their various importance subtypes comes of cell-released from the study mem- of branouscirculating structures human referred EVs in inflammatoryto as exosomes, disorders, microvesicles, and even microparticles, more from theectosomes, recognition on- cosomes,of their presence apoptotic in bodies, body fluids and many [12]. EV-containingother names. Unfortunately, “liquid biopsies” these such terms, as blood even [ 13to-], day,BAL mean [14], urinedifferent [15], things saliva to [13 different], and cerebrospinal investigators, fluid which [16 creates] can be vexing obtained problems in an easy re- latedand minimallyto their nomenclature. invasive way Furthermore, and are seenas specific a promising issues alternativearise when to working regular biopsieswith these [9]. entities,Indeed, whose the comprehensive size and amount characterization often make them of EVs difficult and of to their obtain content as relatively in body fluidspure preparationsmight offer the and key to tocharacterize better understand properly. disease development and treatment. Figure 1. Number of publications per year in PubMed from 1946 to 2021. After the first annual meeting of the International Society of Extracellular Vesicles (ISEV) in 2012, the number of original papers and reviews including any extracellular- vesicle-related terms (exosomes, microvesicles, microparticles, and extracellular vesicles) increased exponentially. EVs: extracellular vesicles; EM: electron microscopy; ISEV: International Society of Extracellular Vesicles; MISEV: Minimal Information for Studies of Extracellular Vesicles. 2. Evolution of the EVs Nomenclature: From 1946 to Today As shown in Figure1, recent decades have seen a sharp increase in the number of scien- tific publications describing the physiological and pathological functions of “extracellular vesicles” (EVs), a collective term covering various subtypes of cell-released membranous structures referred to as exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. Unfortunately, these terms, even today, mean Int. J. Mol. Sci. 2021, 22, 6417 3 of 13 different things to different investigators, which creates vexing problems related to their nomenclature. Furthermore,
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