Extracellular vesicles (EVs) are small structures that are released from cells into the surrounding environment. When originally described their function was mainly linked to waist system. We now know that these structures play an important role in intercellular communication both in physiological and disease contexts. 

 

 

Extracellular Vesicles Explained by EVCA member Graça Raposo
Extracellular Vesicles Explained by EVCA member Gisela D'Angelo
Extracellular Vesicles Explained by EVCA member Christophe Lamaze
Extracellular Vesicles Explained by EVCA member Juan Fálcon
Extracellular Vesicles Explained by EVCA member Gisela D'Angelo in Portuguese
Behind the Scenes of EVCA Members About EVs series

  1. Vasco Ferreira J, Soares AR, Ramalho J, Carvalho CM, Cardoso MH, Pintado P, Carvalho AS, Beck HC, Matthiesen R, Zuzarte M, Girão H, vanNiel G and Pereira P. LAMP2A regulates the loading of proteins into exosomes. Sci Adv 8(12), eabm1140 (2022).
    https://doi.org/10.1126/sciadv.abm1140 

    Exosomes are tiny vesicles released by almost all cell types in complex organisms, acting as messengers by transferring lipids, RNAs, and proteins between cells and even different body parts. This study reveals a mechanism, controlled by a protein called LAMP2A, which determines which proteins get loaded into these exosomes. Interestingly, this process is used to transport signals from oxygen-deprived cells to those with normal oxygen levels. Additionally, by attaching specific sequences to glowing proteins, the researchers could trace how these exosomes move between organs. This discovery can pave the way for customizing exosomes for therapeutic purposes by adding specific protein tags.

  1. Matthiesen R, Gameiro P, Henriques A, Bodo C, Moraes MCS, Costa-Silva B, Cabeçadas J, Gomes da Silva M, Beck HC and Carvalho AS. Extracellular Vesicles in Diffuse Large B Cell Lymphoma: Characterization and Diagnostic Potential. Int J Mol Sci 23(21), 13327 (2022).
    https://doi.org/10.3390/ijms232113327 

The most significant finding of this study is that tiny packages released by cells in the blood, called extracellular vesicles (EVs), contain unique proteins that can accurately identify individuals with Diffuse Large B Cell Lymphoma (DLBCL) from healthy individuals. These EV proteins also appear to hold potential as markers for predicting how well DLBCL patients will fare in terms of survival after treatment. While the study didn't identify specific proteins associated with different DLBCL subtypes, it did reveal differences in how the immune system responds in these subtypes. Overall, this research suggests that analyzing the EV proteome in the blood could be a promising tool for diagnosing DLBCL and predicting patient outcomes. 

  1. Carvalho AS, Moraes MCS, Hyun Na C, Fierro-Monti I, Henriques A, Zahedi S, Bodo C, Tranfield EM, Sousa AL, Farinho A, Vaz Rodrigues L, Pinto P, Bárbara C, Mota L, Tavares de Abreu T, Semedo J, Seixas S, Kumar P, Costa-Silva B, Pandey A and Matthiesen R. Is the Proteome of Bronchoalveolar Lavage Extracellular Vesicles a Marker of Advanced Lung Cancer? Cancers (Basel) 12(11), 3450 (2020).
    https://doi.org/10.3390/cancers12113450 

The key discovery in this study is that the complexity of proteins found in the lung fluid's tiny packages called extracellular vesicles (EVs) is linked to the stage of lung cancer. In simpler terms, the more complex the proteins in these packages, the more advanced the cancer tends to be. This suggests that analyzing these proteins in the lung fluid could help doctors determine how far a person's lung cancer has progressed, which is crucial information for treatment decisions. 

  1. Ferreira I, Machado de Oliveira R, Carvalho AS, Teshima A, Beck HC, Matthiesen R, Costa-Silva B and Macedo MP. Messages from the Small Intestine Carried by Extracellular Vesicles in Prediabetes: A Proteomic Portrait. J Proteome Res 21(4), 910-920 (2022).
    https://doi.org/10.1021/acs.jproteome.1c00353 

  1. Carvalho AS, Carvalho AS, Baeta H, Costa Silva B, Strano Moraes MC, Bodo C, Beck HC, Rodriguez MS, Saraswat M, Pandey A and Matthiesen R. Extra-cellular vesicles carry proteome of cancer hallmarks. Front Biosci 25(3), 398-436 (2020).
    https://doi.org/10.2741/4811 

This study looked at tiny packages called extracellular vesicles (EVs) that cells release to communicate with neighboring cells. These EVs carry important molecules like DNA, RNA, and proteins. In cancer, they can influence cell growth, spreading, and even help tumors hide from the immune system. The study compared the proteins in these EVs with those in whole cells from different cancer types. The study found certain EV proteins that are crucial in cancer and often targeted by cancer treatments. These proteins were found in high amounts in EVs. This might be a problem because it could make cancer treatments less effective if these proteins in EVs distract the treatment. So, understanding how EVs work could help us improve cancer therapies.

  1. Carvalho AS, Baeta H, Henriques AFA, Ejtehadifar M, Tranfield EM, Sousa AL, Farinho A, Silva BC, Cabeçadas J, Gameiro P, Gomes da Silva M, Beck HC and Matthiesen R. Proteomic Landscape of Extracellular Vesicles for Diffuse Large B-Cell Lymphoma Subtyping. Int J Mol Sci 22(20), 11004 (2021).
    https://doi.org/10.3390/ijms222011004 

  1. Bernardino RMM, Leão R, Henrique R, Pinheiro LC, Kumar P, Suravajhala P, Beck HC, Carvalho AS and Matthiesen R. Extracellular Vesicle Proteome in Prostate Cancer: A Comparative Analysis of Mass Spectrometry Studies. Int J Mol Sci 22(24), 13605 (2021).
    https://doi.org/10.3390/ijms222413605 

  1. Couto N, Elzanowska J, Maia J, Batista S, Pereira CE, Beck HC, Carvalho AS, Strano Moraes MC, Carvalho C, Oliveira M, Matthiesen R and Costa-Silva B. IgG+ Extracellular Vesicles Measure Therapeutic Response in Advanced Pancreatic Cancer. Cells 11(18), 2800 (2022).
    https://doi.org/10.3390/cells11182800 

  1. Velosa Ferreira B, Arnault Carneiro E, Pestana C, Barahona F, Caetano J, Lopes R, Lúcio P, Neves M, Beck HC, Carvalho AS, Matthiesen R, Costa-Silva B and João C. Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study. Front Oncol 12, 860849 (2022).
    https://doi.org/10.3389/fonc.2022.860849 

  1. Lopes R, Caetano J, Barahona F, Pestana C, Velosa Ferreira B, Lourencço D, Queirós AC, Bilreiro C, Shemesh N, Beck HC, Carvalho AS, Matthiesen R, Bogen B, Costa-Silva B, Serre K, Carneiro EA and João C. Multiple Myeloma-Derived Extracellular Vesicles Modulate the Bone Marrow Immune Microenvironment. Front Immunol 13, 909880 (2022).
    https://doi.org/10.3389/fimmu.2022.909880 

  1. Mleczko JE, Royo F,  Samuelson I,  Clos-Garcia M,  Williams C,  Cabrera D,  Azparren-Angulo M,  Gonzalez E,  Garcia-Vallicrosa C,  Carobbio S,  Rodriguez-Cuenca S,  Azkargorta M, van Liempd S,  Elortza F,  Vidal-Puig A, Mora S and Falcon-Perez JM. Extracellular vesicles released by steatotic hepatocytes alter adipocyte metabolism. J Extracell Bio 1, e32 (2022).
    https://doi.org/10.1002/jex2.32 

  1. Ibañez-Perez J, Díaz-Nuñez M, Clos-García M, Lainz L, Iglesias M, Díez-Zapirain M, Rabanal A, Bárcena L, González M, Lozano JJ, Marigorta UM, González E, Royo F, Aransay AM, Subiran N, Matorras R, Falcón-Pérez JM. microRNA-based signatures obtained from endometrial fluid identify implantative endometrium. Human Reproduction 37(10), 2375–2391 (2022).
    https://doi.org/10.1093/humrep/deac184 

  1. Las Heras K, Félix RF, Garcia-Vallicrosa C, Igartua M, Santos-Vizcaino E, Falcon-Perez JM and Hernandez RM. Extracellular vesicles from hair follicle-derived mesenchymal stromal cells: isolation, characterization and therapeutic potential for chronic wound healing. Stem Cell Res Ther 13, 147 (2022).
    https://doi.org/10.1186/s13287-022-02824-0 

  1. Azkargorta M, Iloro I, Escobes I, Cabrera D, Falcon-Perez JM, Elortza F and Royo F. Human Serum Extracellular Vesicle Proteomic Profile Depends on the Enrichment Method Employed. Int J Mol Sci 22(20), 11144 (2021).
    https://doi.org/10.3390/ijms222011144 

  1. Bordanaba-Florit G, Royo F, Kruglik SG and Falcón-Pérez JM. Using single-vesicle technologies to unravel the heterogeneity of extracellular vesicles. Nat Protoc 16, 3163–3185 (2021).
    https://doi.org/10.1038/s41596-021-00551-z 

  1. Williams C, Pazos R, Royo F, González E, Roura-Ferrer M, Martinez A, Gamiz J, Reichardt NC and Falcón-Pérez JM. Assessing the role of surface glycans of extracellular vesicles on cellular uptake. Sci Rep 9, 11920 (2019).
    https://doi.org/10.1038/s41598-019-48499-1 

  1. Prieto-Fernández E, Aransay AM, Royo F, González E, Lozano JJ, Santos-Zorrozua B, Macias-Camara N, González M, Garay RP, Benito J, Garcia-Orad A and Falcón-Pérez JM. A Comprehensive Study of Vesicular and Non-Vesicular miRNAs from a Volume of Cerebrospinal Fluid Compatible with Clinical Practice. Theranostics 9(16), 4567-4579 (2019).
    https://doi.org/10.7150/thno.31502  

  1. Royo F, Gil-Carton D, Gonzalez E, Mleczko J, Palomo L, Perez-Cormenzana M, Mayo R, Alonso C and Falcon-Perez JM. Differences in the metabolite composition and mechanical properties of extracellular vesicles secreted by hepatic cellular models. J Extracell Vesicles 8, 1575678 (2019).
    https://doi.org/10.1080/20013078.2019.1575678 

  1. Kruglik SG, Royo F, Guigner JM, Palomo L, Seksek O, Turpin PY, Tatischeff I and Falcón-Pérez JM. Raman tweezers microspectroscopy of circa 100 nm extracellular vesicles. Nanoscale11, 1661-1679 (2019).
    https://doi.org/10.1039/C8NR04677H 

  1. Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, Elortza F, Lu SC, Mato JM and Falcon-Perez JM. Characterization and Comprehensive Proteome Profiling of Exosomes Secreted by Hepatocytes. J Proteome Res 7(12), 5157-5166 (2008).
    https://doi.org/10.1021/pr8004887 

  1. Jneid B, Bochnakian A, Hoffmann C, Delisle F, Djacoto E, Sirven P, Denizeau J, Sedlik C, Gerber-Ferder Y, Fiore F, Akyol R, Brousse C, Kramer R, Walters I, Carlioz S, Salmon H, Malissen B, Dalod M, Piaggio E, Manel N. Selective STING stimulation in dendritic cells primes antitumor T cell responses. Sci Immunol, 8:eabn6612 (2023).
    https://doi.org/10.1126/sciimmunol.abn6612 

  1. Tulukcuoglu GE, Lakis E, Hajji I, Martin E, Champ J, Rampanou A, Pierga JY, Viovy JL, Proudhon C, Bidard FC and Descroix S. Deciphering HER2-HER3 Dimerization at the Single CTC Level: A Microfluidic Approach. Cancers (Basel), 14:1890 (2022).
    https://doi.org/10.3390/cancers14081890 

  1. Hurbain I, Macé AS, Romao M, Prince E, Sengmanivong L, Ruel L, Basto R, Thérond PP, Raposo G and D'Angelo G. Microvilli-derived extracellular vesicles carry Hedgehog morphogenic signals for Drosophila wing imaginal disc development. Curr Biol 32(2), 361-373.e6 (2021).
    https://doi.org/10.1016/j.cub.2021.11.023 

  1. Mathieu M, Martin-Jaular L, Lavieu G and Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21, 9–17 (2019).
    https://doi.org/10.1038/s41556-018-0250-9 

  1. van Niel G, D'Angelo G and Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19, 213-228 (2018).
    https://doi.org/10.1038/nrm.2017.125 

  1. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M and Théry C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA 113(8), E968-E977 (2016).
    https://doi.org/10.1073/pnas.152123011 

  1. Lo Cicero A, Delevoye C, Gilles-Marsens F, Loew D, Dingli F, Guere C, Andre N, Vie K, van Niel G and Raposo G. Exosomes released by keratinocytes modulate melanocyte pigmentation. Nat Commun 6, 7506 (2015).
    https://doi.org/10.1038/ncomms8506 

Primary keratinocytes secrete exosomes that modulate the pigmentation status of melanocytes. This manuscript shows for the first time that exosomes are essential in skin homeostasis and the maintenance of pigmentation. Exosomes were shown to induce transcription factors and activate genes affecting melanosome structure and function. These effects are attributed to particular miRNAs associated with the exosomes. This study opened a pathway to develop cosmetic treatments to modulate pigmentation.

  1. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF and Thery C. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biology 12, 19–30 (2010).
    https://doi.org/10.1038/ncb2000 

  1. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H and Raposo G. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101, 9683-9688 (2004).
    https://doi.org/10.1073/pnas.030841310 

Prions can be secreted from cells in association with exosomes. This manuscript shows for the first time that exosomes carrying infectious Prions are able to induce neurodegenerative disease in mouse models. This study provided the underpinnings for a wide range of studies, from basic to applied, to further understand the pathophysiology of neurodegenerative diseases and the role of extracellular vesicles as purveyors of the infection cycle.

  1. Raposo G, Nijman HW, Stoorvogel W, Leijendekker R, Harding CV, Melief CJ and Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183, 1161-1172 (1996).
    https://doi.org/10.1084/jem.183.3.1161 

This is the first study to reveal that exosomes operate as signaling entities.  This manuscript shows that cells from the immune system, such as B lymphocytes, secrete endosome-derived exosomes. Importantly, exosomes derived from both human and murine B lymphocytes induced antigen-specific MHC class II-restricted T cell responses, suggesting a role for exosomes in antigen presentation in vivo. 

 

Ilustrations by Ana Soares

 

Extracelular Vesicles: Microvesicle and Exosomes

 

Extracelular Vesicles are involved in many physiological and disease contexts.

 

 

 

 

 

Extracellular Vesicles - the cells' secret messengers - Scientific version by Arkitek Scientific (use your mouse to pan around in the movie)
Exosomes are key for pancreatic cancer cell–cell communication and targeted metastasis by Research Square
EXOSOMES: A Rising Tool In Regenerative Science by Kosheeka: BioManufacturing Services
What is the therapeutic potential of exosomes?