Extracellular vesicles - on the cusp of a new language in the biological sciences

Abstract

Extracellular vesicles (EVs) play a key role both in physiological balance and homeostasis and in disease processes through their ability to participate in intercellular signaling and communication. An ever-expanding knowledge pool and a myriad of functional properties ascribed to EVs point to a new language of communication in biological systems that has opened a path for the discovery and implementation of novel diagnostic applications. EVs originate in the endosomal network and via non-random shedding from the plasma membrane by mechanisms that allow the packaging of functional cargoes, including proteins, lipids, and genetic materials. Deciphering the molecular mechanisms that govern packaging, secretion and targeted delivery of extracellular vesicle-borne cargo will be required to establish EVs as important signaling entities, especially when ascribing functional properties to a heterogeneous population of vesicles. Several molecular cascades operate within the endosomal network and at the plasma membrane that recognize and segregate cargos as a prelude to vesicle budding and release. EVs are transferred between cells and operate as vehicles in biological fluids within tissues and within the microenvironment where they are responsible for short- and long-range targeted information. In this review, we focus on the remarkable capacity of EVs to establish a dialogue between cells and within tissues, often operating in parallel to the endocrine system, we highlight selected examples of past and recent studies on the functions of EVs in health and disease.

Keywords

Extracellular vesicles / biogenesis / intercellular communication / endocrine / homeostasis

References

[1] Duve C, Wattiaux R. Functions of lysosomes.Annu Rev Physiol1966;28:435-92

[2] Duve C. The significance of lysosomes in pathology and medicine.Proc Inst Med Chic1966;26:73-6

[3] Brown MS.Michael S. Brown, MD, Joseph L. Goldstein, MD. 1985 Nobel laureates in medicine.J Investig Med1996;44:14-23.

[4] Schekman R.23 genes, 23 years later.Cell2004;116:S13-5, 1 p following S19

[5] Couch Y,Di Vizio D.A brief history of nearly EV-erything - the rise and rise of extracellular vesicles.J Extracell Vesicles2021;10:e12144 PMCID:PMC8681215

[6] Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles.Nat Rev Mol Cell Biol2018;19:213-28

[7] Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles.Nat Rev Mol Cell Biol2022;23:369-82

[8] Cicero A, Stahl PD, Raposo G. Extracellular vesicles shuffling intercellular messages: for good or for bad.Curr Opin Cell Biol2015;35:69-77

[9] Stegmayr B.Promotive effect on human sperm progressive motility by prostasomes. Urol Res 1982;10:253-7.

[10] Pan YC.Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 1983;33:967–78..Cell1983;33:967-78

[11] Pan BT,Wu C,Johnstone RM.Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes.J Cell Biol1985;101:942-8 PMCID:PMC2113705

[12] Harding C,Stahl P.Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. Journal of Cell Biology 1983;97:329-39. PMCID:PMC2112509

[13] Harding C,Stahl P.Endocytosis and intracellular processing of transferrin and colloidal-gold transferrin in rat reticulocytes : demonstration of a pathway for receptor shedding.Eur J Cell Biol1984;35:256-63

[14] Díaz-Garrido N,Baldomà L.Microbiota-derived extracellular vesicles in interkingdom communication in the gut.J Extracell Vesicles2021;10:e12161 PMCID:PMC8568775

[15] Frühbeis C,Kuo WP.Extracellular vesicles as mediators of neuron-glia communication.Front Cell Neurosci2013;7:182 PMCID:PMC3812991

[16] Raposo G,Stoorvogel W.B lymphocytes secrete antigen-presenting vesicles.J Exp Med1996;183:1161-72 PMCID:PMC2192324

[17] Zitvogel L,Lozier A.Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes.Nat Med1998;4:594-600

[18] Lo Cicero A,Gilles-Marsens F.Exosomes released by keratinocytes modulate melanocyte pigmentation.Nat Commun2015;6:7506 PMCID:PMC4491833

[19] Liu Y,Wang J.Exosomes as a novel pathway for regulating development and diseases of the skin.Biomed Rep2018;8:207-14 PMCID:PMC5867470

[20] Deng ZB,Hardy RW.Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance.Diabetes2009;58:2498-505 PMCID:PMC2768161

[21] Wang J,Zhang Z.Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance.Cell Metab2022;34:1264-1279.e8

[22] Nederveen JP,Di Carlo A,Tarnopolsky MA.Extracellular vesicles and exosomes: insights from exercise science.Front Physiol2020;11:604274 PMCID:PMC7882633

[23] Sabaratnam R,Højlund K.Factors mediating exercise-induced organ crosstalk.Acta Physiol2022;234:e13766

[24] Johnstone RM.Exosomes biological significance: a concise review.Blood Cells Mol Dis2006;36:315-21

[25] Verweij FJ,Arras G.Live Tracking of inter-organ communication by endogenous exosomes in vivo.Dev Cell2019;48:573-589.e4

[26] Iraci N,Leonardi T.Extracellular vesicles are independent metabolic units with asparaginase activity.Nat Chem Biol2017;13:951-5 PMCID:PMC5563455

[27] Rajendran L,Barr MM.Emerging roles of extracellular vesicles in the nervous system.J Neurosci2014;34:15482-9 PMCID:PMC4228143

[28] Chaput N.Exosomes: immune properties and potential clinical implementations.Semin Immunopathol2011;33:419-40

[29] Besse B,Lapierre V.Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC.Oncoimmunology2016;5:e1071008 PMCID:PMC4839329

[30] Keshtkar S,Ghahremani MH.Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine.Stem Cell Res Ther2018;9:63 PMCID:PMC5845209

[31] Tian T,He C.Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia.Theranostics2021;11:6507-21 PMCID:PMC8120222

[32] Chen B,Zhao B.Stem Cell-derived extracellular vesicles as a novel potential therapeutic tool for tissue repair.Stem Cells Transl Med2017;6:1753-8 PMCID:PMC5689748

[33] Martin C,Malnou CE.Placental extracellular vesicles in maternal-fetal communication during pregnancy.Biochem Soc Trans2022;50:1785-95

[34] Hoshino A,Shen TL.Tumour exosome integrins determine organotropic metastasis.Nature2015;527:329-35 PMCID:PMC4788391

[35] Pérez PS,Duette GA.Extracellular vesicles and chronic inflammation during HIV infection.J Extracell Vesicles2019;8:1687275 PMCID:PMC6963413

[36] Hill AF.Extracellular vesicles and neurodegenerative diseases.J Neurosci2019;39:9269-73 PMCID:PMC6867808

[37] Troyer Z,Tabler CO.Extracellular vesicles carry SARS-CoV-2 spike protein and serve as decoys for neutralizing antibodies.J Extracell Vesicles2021;10:e12112 PMCID:PMC8213968

[38] Wiklander OPB,Lötvall J,El Andaloussi S.Advances in therapeutic applications of extracellular vesicles.Sci Transl Med2019;11 PMCID:PMC7104415

[39] Witwer KW,O'Driscoll L.Updating MISEV: evolving the minimal requirements for studies of extracellular vesicles.J Extracell Vesicles2021;10:e12182 PMCID:PMC8710080

[40] D'Angelo G,Nishimura T.Protrusion-derived vesicles: new subtype of EVs?.Nat Rev Mol Cell Biol2023;24:81-2

[41] Luxmi R.Cilia-derived vesicles: an ancient route for intercellular communication.Semin Cell Dev Biol2022;129:82-92 PMCID:PMC9378432

[42] Yu S.Migrasome biogenesis and functions.FEBS J2022;289:7246-54 PMCID:PMC9786993

[43] Santavanond JP,Atkin-smith GK.Apoptotic bodies: mechanism of formation, isolation and functional relevance. In: Mathivanan S, Fonseka P, Nedeva C, Atukorala I, editors. New Frontiers: Extracellular Vesicles. Cham: Springer International Publishing; 2021. pp. 61-88.

[44] Rai A,Xu R,Suwakulsiri W.Secreted midbody remnants are a class of extracellular vesicles molecularly distinct from exosomes and microparticles.Commun Biol2021;4:400 PMCID:PMC7994562

[45] Zhang Q,Jeppesen DK.Transfer of functional cargo in exomeres.Cell Rep2019;27:940-954.e6 PMCID:PMC6559347

[46] Tóth EÁ,Visnovitz T.Formation of a protein corona on the surface of extracellular vesicles in blood plasma.J Extracell Vesicles2021;10:e12140 PMCID:PMC8439280

[47] Edgar JR,Nishimura S,Robinson MS.Tetherin is an exosomal tether.Elife2016;5:e17180 PMCID:PMC5033606

[48] Théry C,Raposo G.Isolation and characterization of exosomes from cell culture supernatants and biological fluids.Curr Protoc Cell Biol2006;3:

[49] Verweij FJ,Boulanger CM.The power of imaging to understand extracellular vesicle biology in vivo.Nat Methods2021;18:1013-26 PMCID:PMC8796660

[50] Février B.Exosomes: endosomal-derived vesicles shipping extracellular messages.Curr Opin Cell Biol2004;16:415-21

[51] Sidhom K,Saleem A.A review of exosomal isolation methods: is size exclusion chromatography the best option?.Int J Mol Sci2020;21:6466 PMCID:PMC7556044

[52] Zhang H.Asymmetric-flow field-flow fractionation technology for exomere and small extracellular vesicle separation and characterization.Nat Protoc2019;14:1027-53 PMCID:PMC6733524

[53] Pariset E,Millet A.Extracellular vesicles: isolation methods.Adv Biosyst2017;1:e1700040

[54] Hurley JH,Lee HH,Wollert T.Piecing together the ESCRTs.Biochem Soc Trans2009;37:161-6

[55] Vietri M,Stenmark H.The many functions of ESCRTs.Nat Rev Mol Cell Biol2020;21:25-42

[56] Nabhan JF,Oh RS,Lu Q.Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein.Proc Natl Acad Sci U S A2012;109:4146-51 PMCID:PMC3306724

[57] Trajkovic K,Chiantia S.Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 2008;319:1244-7.

[58] van Niel G,Simoes S.The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis.Dev Cell2011;21:708-21 PMCID:PMC3199340

[59] Baietti MF,Mortier E.Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.Nat Cell Biol2012;14:677-85

[60] Muralidharan-Chari V,Plou C.ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles.Curr Biol2009;19:1875-85 PMCID:PMC3150487

[61] Hurbain I,Romao M.Microvilli-derived extracellular vesicles carry Hedgehog morphogenic signals for Drosophila wing imaginal disc development.Curr Biol2022;32:361-373.e6

[62] Ostrowski M,Krumeich S.Rab27a and Rab27b control different steps of the exosome secretion pathway.Nat Cell Biol2010;12:19-30; sup pp 1

[63] Delevoye C,Raposo G.Lysosome-related organelles as functional adaptations of the endolysosomal system.Curr Opin Cell Biol2019;59:147-58 PMCID:PMC6726539

[64] Mobius W,van Donselaar EG.Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O.J Histochem Cytochem2002;50:43-55

[65] Buschow SI,van Niel G.MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways.Traffic2009;10:1528-42

[66] Verweij FJ,George AE.ER membrane contact sites support endosomal small GTPase conversion for exosome secretion.J Cell Biol2022;221 PMCID:PMC9507465

[67] Verweij FJ,Jimenez CR.Quantifying exosome secretion from single cells reveals a modulatory role for GPCR signaling.J Cell Biol2018;217:1129-42 PMCID:PMC5839777

[68] Atukorala I.The role of post-translational modifications in targeting protein cargo to extracellular vesicles. In: Mathivanan S, Fonseka P, Nedeva C, Atukorala I, editors. New Frontiers: Extracellular Vesicles, Vol 97. Cham: Springer International Publishing; 2021. pp. 45-60.

[69] Buschow SI,Wubbolts R.Exosomes contain ubiquitinated proteins.Blood Cells Mol Dis2005;35:398-403

[70] Li Y,Yang F.Complex N-glycan promotes CD133 mono-ubiquitination and secretion.FEBS Lett2019;593:719-31

[71] Villarroya-Beltri C,Sánchez-Cabo F.Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs.Nat Commun2013;4:2980 PMCID:PMC3905700

[72] Liu XM,Schekman R.Selective sorting of microRNAs into exosomes by phase-separated YBX1 condensates.Elife2021;10 PMCID:PMC8612733

[73] Fabbiano F,Gurrieri E,Notarangelo M.RNA packaging into extracellular vesicles: An orchestra of RNA-binding proteins?.J Extracell Vesicles2020;10:e12043 PMCID:PMC7769857

[74] van Niel G,Candalh C.Intestinal epithelial cells secrete exosome-like vesicles.Gastroenterology2001;121:337-49

[75] Matsui T,Hiragi S,Fukuda M.ALIX and ceramide differentially control polarized small extracellular vesicle release from epithelial cells.EMBO Rep2021;22:e51475 PMCID:PMC8097368

[76] Neven KY,Bollati V.Extracellular vesicles: how the external and internal environment can shape cell-to-cell communication.Curr Environ Health Rep2017;4:30-7

[77] Korenkova O,Zurzolo C.Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?.Cell Stress2020;4:30-43 PMCID:PMC6997949

[78] Vechetti IJ Jr,Wen Y.Mechanical overload-induced muscle-derived extracellular vesicles promote adipose tissue lipolysis.FASEB J2021;35:e21644 PMCID:PMC8607211

[79] Mwase C,O'Sullivan MJ.Mechanical compression of human airway epithelial cells induces release of extracellular vesicles containing tenascin C.Cells2022;11:256 PMCID:PMC8774246

[80] Lanna A,D'Ambra C.An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.Nat Cell Biol2022;24:1461-74 PMCID:PMC7613731

[81] Kalargyrou AA,Smith AJ,Pearson RA.Extracellular vesicles in the retina - putative roles in physiology and disease.Front Mol Neurosci2022;15:1042469 PMCID:PMC9877344

[82] Palmulli R,Raposo G,van Niel G.In vitro interaction of melanoma-derived extracellular vesicles with collagen.Int J Mol Sci2023;24:3703 PMCID:PMC9964759

[83] Arthur P,Nathani A.Bioengineering human pluripotent stem cell-derived retinal organoids and optic vesicle-containing brain organoids for ocular diseases.Cells2022;11:3429 PMCID:PMC9653705

[84] Stahl PD.Extracellular vesicles: exosomes and microvesicles, integrators of homeostasis.Physiology2019;34:169-77

[85] Domingues L,Gilles-Marsens F.Coupling of melanocyte signaling and mechanics by caveolae is required for human skin pigmentation.Nat Commun2020;11:2988 PMCID:PMC7293304

[86] Yamaguchi Y,Hearing VJ.The regulation of skin pigmentation.J Biol Chem2007;282:27557-61

[87] Wang WM,Jin HZ.Exosomes in chronic inflammatory skin diseases and skin tumors.Exp Dermatol2019;28:213-8

[88] Lattmann E.The role of extracellular vesicles in melanoma progression.Cancers2022;14:3086 PMCID:PMC9264817

[89] Carvalho-Silva LT,Sá JO.Extracellular vesicles in carcinoma microenvironment.Biochem Soc Trans2023;51:771-81

[90] Choi EJ,Cho EG.Extracellular vesicles derived from senescent fibroblasts attenuate the dermal effect on keratinocyte differentiation.Int J Mol Sci2020;21:1022 PMCID:PMC7037765

[91] Casado-Díaz A,Dorado G.Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing.Front Bioeng Biotechnol2020;8:146 PMCID:PMC7062641

[92] Brown L,Prados-Rosales R.Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi.Nat Rev Microbiol2015;13:620-30 PMCID:PMC4860279

[93] Cui Y,He Y.Plant extracellular vesicles.Protoplasma2020;257:3-12

[94] Théry C,Segura E.Membrane vesicles as conveyors of immune responses.Nat Rev Immunol2009;9:581-93

[95] Rus Jacquet A, Tancredi JL, Lemire AL, DeSantis MC, Li WP, O'Shea EK. The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease.Elife2021;10 PMCID:PMC8514240

[96] Ying W,Dos Reis FCG.MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice.Cell Metab2021;33:781-790.e5 PMCID:PMC8035248

[97] Whitham M,Friedrichsen M.Extracellular vesicles provide a means for tissue crosstalk during exercise.Cell Metab2018;27:237-251.e4

[98] Liégeois S,Garnier JM,Labouesse M.The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans.J Cell Biol2006;173:949-61 PMCID:PMC2063919

[99] Poret A, Dibsy R, Merida P, Trausch A, Inamdar K, Muriaux D. Extracellular vesicles containing the I-BAR protein IRSp53 are released from the cell plasma membrane in an Arp2/3 dependent manner.Biol Cell2022;114:259-75