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http://dx.doi.org/10.14348/molcells.2022.0110

Extracellular Vesicles as an Endocrine Mechanism Connecting Distant Cells  

Kita, Shunbun (Department of Metabolic Medicine, Graduate School of Medicine, Osaka University)
Shimomura, Iichiro (Department of Metabolic Medicine, Graduate School of Medicine, Osaka University)
Publication Information
Molecules and Cells / v.45, no.11, 2022 , pp. 771-780 More about this Journal
Abstract
The field of extracellular vesicles (EVs) has expanded tremendously over the last decade. The role of cell-to-cell communication in neighboring or distant cells has been increasingly ascribed to EVs generated by various cells. Initially, EVs were thought to a means of cellular debris or disposal system of unwanted cellular materials that provided an alternative to autolysis in lysosomes. Intercellular exchange of information has been considered to be achieved by well-known systems such as hormones, cytokines, and nervous networks. However, most research in this field has searched for and found evidence to support paracrine or endocrine roles of EV, which inevitably leads to a new concept that EVs are synthesized to achieve their paracrine or endocrine purposes. Here, we attempted to verify the endocrine role of EV production and their contents, such as RNAs and bioactive proteins, from the regulation of biogenesis, secretion, and action mechanisms while discussing the current technical limitations. It will also be important to discuss how blood EV concentrations are regulated as if EVs are humoral endocrine machinery.
Keywords
adiponectin; ceramide; exosome; extracellular vesicles; syntenin; tetraspanin;
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1 van Niel, G., D'Angelo, G., and Raposo, G. (2018). Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213-228.   DOI
2 Witwer, K.W., Buzas, E.I., Bemis, L.T., Bora, A., Lasser, C., Lotvall, J., Nolte-'t Hoen, E.N., Piper, M.G., Sivaraman, S., Skog, J., et al. (2013). Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2, 10.3402/jev.v2i0.20360.   DOI
3 Yao, R.W., Wang, Y., and Chen, L.L. (2019). Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542-551.   DOI
4 Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C.L., Yoshida, Y., Matsumoto, N., Yoshida, Y., Katayama, A., Wada, J., Seki, M., et al. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Sci. Rep. 12, 6522.   DOI
5 Gurunathan, S., Kang, M.H., and Kim, J.H. (2021). A comprehensive review on factors influences biogenesis, functions, therapeutic and clinical implications of exosomes. Int. J. Nanomedicine 16, 1281-1312.   DOI
6 Hurley, J.H., Boura, E., Carlson, L.A., and Rozycki, B. (2010). Membrane budding. Cell 143, 875-887.   DOI
7 Hessvik, N.P. and Llorente, A. (2018). Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193-208.   DOI
8 Jadli, A.S., Ballasy, N., Edalat, P., and Patel, V.B. (2020). Inside (sight) of tiny communicator: exosome biogenesis, secretion, and uptake. Mol. Cell. Biochem. 467, 77-94.   DOI
9 Hikita, T., Miyata, M., Watanabe, R., and Oneyama, C. (2018). Sensitive and rapid quantification of exosomes by fusing luciferase to exosome marker proteins. Sci. Rep. 8, 14035.   DOI
10 Jeon, H.Y., Das, S.K., Dasgupta, S., Emdad, L., Sarkar, D., Kim, S.H., Lee, S.G., and Fisher, P.B. (2013). Expression patterns of MDA-9/syntenin during development of the mouse embryo. J. Mol. Histol. 44, 159-166.   DOI
11 Zimmermann, P., Tomatis, D., Rosas, M., Grootjans, J., Leenaerts, I., Degeest, G., Reekmans, G., Coomans, C., and David, G. (2001). Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments. Mol. Biol. Cell 12, 339-350.   DOI
12 Wei, D., Zhan, W., Gao, Y., Huang, L., Gong, R., Wang, W., Zhang, R., Wu, Y., Gao, S., and Kang, T. (2021). RAB31 marks and controls an ESCRTindependent exosome pathway. Cell Res. 31, 157-177.   DOI
13 Witwer, K.W. and Thery, C. (2019). Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J. Extracell. Vesicles 8, 1648167.   DOI
14 Xie, S., Zhang, Q., and Jiang, L. (2022). Current knowledge on exosome biogenesis, cargo-sorting mechanism and therapeutic implications. Membranes (Basel) 12, 498.   DOI
15 Kita, S., Fukuda, S., Maeda, N., and Shimomura, I. (2019a). Native adiponectin in serum binds to mammalian cells expressing T-cadherin, but not AdipoRs or calreticulin. Elife 8, e48675.   DOI
16 Savina, A., Furlan, M., Vidal, M., and Colombo, M.I. (2003). Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J. Biol. Chem. 278, 20083-20090.   DOI
17 Johmura, Y., Yamanaka, T., Omori, S., Wang, T.W., Sugiura, Y., Matsumoto, M., Suzuki, N., Kumamoto, S., Yamaguchi, K., Hatakeyama, S., et al. (2021). Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science 371, 265-270.   DOI
18 Kadota, T., Fujita, Y., Yoshioka, Y., Araya, J., Kuwano, K., and Ochiya, T. (2018). Emerging role of extracellular vesicles as a senescence-associated secretory phenotype: insights into the pathophysiology of lung diseases. Mol. Aspects Med. 60, 92-103.   DOI
19 Kalluri, R. and LeBleu, V.S. (2020). The biology, function, and biomedical applications of exosomes. Science 367, eaau6977.   DOI
20 Kashyap, R., Balzano, M., Lechat, B., Lambaerts, K., Egea-Jimenez, A.L., Lembo, F., Fares, J., Meeussen, S., Kugler, S., Roebroek, A., et al. (2021). Syntenin-knock out reduces exosome turnover and viral transduction. Sci. Rep. 11, 4083.   DOI
21 Alvarez-Erviti, L., Seow, Y., Schapira, A.H., Gardiner, C., Sargent, I.L., Wood, M.J., and Cooper, J.M. (2011). Lysosomal dysfunction increases exosomemediated alpha-synuclein release and transmission. Neurobiol. Dis. 42, 360-367.   DOI
22 Mathieu, M., Martin-Jaular, L., Lavieu, G., and Thery, C. (2019). Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 21, 9-17.   DOI
23 Kita, S., Maeda, N., and Shimomura, I. (2019b). Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J. Clin. Invest. 129, 4041-4049.   DOI
24 Kojima, R., Bojar, D., Rizzi, G., Hamri, G.C.E., El-Baba, M.D., Saxena, P., Auslander, S., Tan, K.R., and Fussenegger, M. (2018). Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment. Nat. Commun. 9, 1305.   DOI
25 Luo, W., Dai, Y., Chen, Z., Yue, X., Andrade-Powell, K.C., and Chang, J. (2020). Spatial and temporal tracking of cardiac exosomes in mouse using a nano-luciferase-CD63 fusion protein. Commun. Biol. 3, 114.   DOI
26 Matsumoto, A., Takahashi, Y., Chang, H.Y., Wu, Y.W., Yamamoto, A., Ishihama, Y., and Takakura, Y. (2020). Blood concentrations of small extracellular vesicles are determined by a balance between abundant secretion and rapid clearance. J. Extracell. Vesicles 9, 1696517.   DOI
27 Misawa, T., Tanaka, Y., Okada, R., and Takahashi, A. (2020). Biology of extracellular vesicles secreted from senescent cells as senescence-associated secretory phenotype factors. Geriatr. Gerontol. Int. 20, 539-546.   DOI
28 Sheldon, H., Heikamp, E., Turley, H., Dragovic, R., Thomas, P., Oon, C.E., Leek, R., Edelmann, M., Kessler, B., Sainson, R.C., et al. (2010). New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116, 2385-2394.
29 Skotland, T., Sandvig, K., and Llorente, A. (2017). Lipids in exosomes: current knowledge and the way forward. Prog. Lipid Res. 66, 30-41.   DOI
30 Stuffers, S., Sem Wegner, C., Stenmark, H., and Brech, A. (2009). Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10, 925-937.   DOI
31 Choezom, D. and Gross, J.C. (2022). Neutral sphingomyelinase 2 controls exosome secretion by counteracting V-ATPase-mediated endosome acidification. J. Cell Sci. 135, jcs259324.   DOI
32 Andreu, Z. and Yanez-Mo, M. (2014). Tetraspanins in extracellular vesicle formation and function. Front. Immunol. 5, 442.
33 Balatskaya, M.N., Sharonov, G.V., Baglay, A.I., Rubtsov, Y.P., and Tkachuk, V.A. (2019). Different spatiotemporal organization of GPI-anchored T-cadherin in response to low-density lipoprotein and adiponectin. Biochim. Biophys. Acta Gen. Subj. 1863, 129414.   DOI
34 Castano, C., Kalko, S., Novials, A., and Parrizas, M. (2018). Obesityassociated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc. Natl. Acad. Sci. U. S. A. 115, 12158-12163.   DOI
35 Colombo, M., Raposo, G., and Thery, C. (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255-289.   DOI
36 Dinkins, M.B., Enasko, J., Hernandez, C., Wang, G., Kong, J., Helwa, I., Liu, Y., Terry, A.V., and Bieberich, E. (2016). Neutral sphingomyelinase-2 deficiency ameliorates Alzheimer's disease pathology and improves cognition in the 5XFAD mouse. J. Neurosci. 36, 8653-8667.   DOI
37 El Andaloussi, S., Mager, I., Breakefield, X.O., and Wood, M.J. (2013). Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 12, 347-357.   DOI
38 Kawada-Horitani, E., Kita, S., Okita, T., Nakamura, Y., Nishida, H., Honma, Y., Fukuda, S., Tsugawa-Shimizu, Y., Kozawa, J., Sakaue, T., et al. (2022). Human adipose-derived mesenchymal stem cells prevent type 1 diabetes induced by immune checkpoint blockade. Diabetologia 65, 1185-1197.   DOI
39 Kita, S. and Shimomura, I. (2021). Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes. J. Biochem. 169, 173-179.   DOI
40 Mateescu, B., Kowal, E.J., van Balkom, B.W., Bartel, S., Bhattacharyya, S.N., Buzas, E.I., Buck, A.H., de Candia, P., Chow, F.W., Das, S., et al. (2017). Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper. J. Extracell. Vesicles 6, 1286095.   DOI
41 Miao, Y., Li, G., Zhang, X., Xu, H., and Abraham, S.N. (2015). A TRP channel senses lysosome neutralization by pathogens to trigger their expulsion. Cell 161, 1306-1319.   DOI
42 Murrow, L., Malhotra, R., and Debnath, J. (2015). ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function. Nat. Cell Biol. 17, 300-310.   DOI
43 Obata, Y., Kita, S., Koyama, Y., Fukuda, S., Takeda, H., Takahashi, M., Fujishima, Y., Nagao, H., Masuda, S., Tanaka, Y., et al. (2018). Adiponectin/ T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release. JCI Insight 3, e99680.   DOI
44 Poupardin, R., Wolf, M., and Strunk, D. (2021). Adherence to minimal experimental requirements for defining extracellular vesicles and their functions. Adv. Drug Deliv. Rev. 176, 113872.   DOI
45 Salminen, A., Kaarniranta, K., and Kauppinen, A. (2020). Exosomal vesicles enhance immunosuppression in chronic inflammation: impact in cellular senescence and the aging process. Cell. Signal. 75, 109771.   DOI
46 Ostrowski, M., Carmo, N.B., Krumeich, S., Fanget, I., Raposo, G., Savina, A., Moita, C.F., Schauer, K., Hume, A.N., Freitas, R.P., et al. (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19-30; sup pp 1-13.
47 Chen, G., Huang, A.C., Zhang, W., Zhang, G., Wu, M., Xu, W., Yu, Z., Yang, J., Wang, B., Sun, H., et al. (2018). Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382-386.   DOI
48 Murillo, O.D., Thistlethwaite, W., Rozowsky, J., Subramanian, S.L., Lucero, R., Shah, N., Jackson, A.R., Srinivasan, S., Chung, A., Laurent, C.D., et al. (2019). exRNA Atlas analysis reveals distinct extracellular RNA cargo types and their carriers present across human biofluids. Cell 177, 463-477.e15.   DOI
49 Nakamura, Y., Kita, S., Tanaka, Y., Fukuda, S., Obata, Y., Okita, T., Nishida, H., Takahashi, Y., Kawachi, Y., Tsugawa-Shimizu, Y., et al. (2020). Adiponectin stimulates exosome release to enhance mesenchymal stem-cell-driven therapy of heart failure in mice. Mol. Ther. 28, 2203-2219.   DOI
50 O'Brien, K., Breyne, K., Ughetto, S., Laurent, L.C., and Breakefield, X.O. (2020). RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat. Rev. Mol. Cell Biol. 21, 585-606.   DOI
51 Dinkins, M.B., Dasgupta, S., Wang, G., Zhu, G., and Bieberich, E. (2014). Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol. Aging 35, 1792-1800.   DOI
52 Clayton, A., Court, J., Navabi, H., Adams, M., Mason, M.D., Hobot, J.A., Newman, G.R., and Jasani, B. (2001). Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J. Immunol. Methods 247, 163-174.   DOI
53 Colombo, M., Moita, C., van Niel, G., Kowal, J., Vigneron, J., Benaroch, P., Manel, N., Moita, L.F., Thery, C., and Raposo, G. (2013). Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553-5565.
54 Devis-Jauregui, L., Eritja, N., Davis, M.L., Matias-Guiu, X., and Llobet-Navas, D. (2021). Autophagy in the physiological endometrium and cancer. Autophagy 17, 1077-1095.   DOI
55 Eitan, E., Green, J., Bodogai, M., Mode, N.A., Baek, R., Jorgensen, M.M., Freeman, D.W., Witwer, K.W., Zonderman, A.B., Biragyn, A., et al. (2017). Age-related changes in plasma extracellular vesicle characteristics and internalization by leukocytes. Sci. Rep. 7, 1342.   DOI
56 Eitan, E., Suire, C., Zhang, S., and Mattson, M.P. (2016). Impact of lysosome status on extracellular vesicle content and release. Ageing Res. Rev. 32, 65-74.   DOI
57 Fabbiano, F., Corsi, J., Gurrieri, E., Trevisan, C., Notarangelo, M., and D'Agostino, V.G. (2020). RNA packaging into extracellular vesicles: an orchestra of RNA-binding proteins? J. Extracell. Vesicles 10, e12043.
58 Fader, C.M., Sanchez, D.G., Mestre, M.B., and Colombo, M.I. (2009). TIVAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim. Biophys. Acta 1793, 1901-1916.   DOI
59 Rider, M.A., Hurwitz, S.N., and Meckes, D.G. (2016). ExtraPEG: a polyethylene glycol-based method for enrichment of extracellular vesicles. Sci. Rep. 6, 23978.   DOI
60 Phuyal, S., Hessvik, N.P., Skotland, T., Sandvig, K., and Llorente, A. (2014). Regulation of exosome release by glycosphingolipids and flotillins. FEBS J. 281, 2214-2227.   DOI
61 Roucourt, B., Meeussen, S., Bao, J., Zimmermann, P., and David, G. (2015). Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res. 25, 412-428.   DOI
62 Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., Matsumoto, N., Yoshida, Y., Mikawa, R., Katayama, A., et al. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat. Aging 1, 1117-1126.   DOI
63 Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M.T., Obuse, C., et al. (2017). Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat. Commun. 8, 15287.   DOI
64 Takasugi, M., Okada, R., Takahashi, A., Virya Chen, D., Watanabe, S., and Hara, E. (2017). Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729.
65 Tanaka, Y., Kita, S., Nishizawa, H., Fukuda, S., Fujishima, Y., Obata, Y., Nagao, H., Masuda, S., Nakamura, Y., Shimizu, Y., et al. (2019). Adiponectin promotes muscle regeneration through binding to T-cadherin. Sci. Rep. 9, 16.   DOI
66 Chairoungdua, A., Smith, D.L., Pochard, P., Hull, M., and Caplan, M.J. (2010). Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J. Cell Biol. 190, 1079-1091.   DOI
67 Baietti, M.F., Zhang, Z., Mortier, E., Melchior, A., Degeest, G., Geeraerts, A., Ivarsson, Y., Depoortere, F., Coomans, C., Vermeiren, E., et al. (2012). Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 14, 677-685.   DOI
68 Bari, R., Guo, Q., Xia, B., Zhang, Y.H., Giesert, E.E., Levy, S., Zheng, J.J., and Zhang, X.A. (2011). Tetraspanins regulate the protrusive activities of cell membrane. Biochem. Biophys. Res. Commun. 415, 619-626.   DOI
69 Cashikar, A.G. and Hanson, P.I. (2019). A cell-based assay for CD63-containing extracellular vesicles. PLoS One 14, e0220007.   DOI
70 Sidhom, K., Obi, P.O., and Saleem, A. (2020). A review of exosomal isolation methods: is size exclusion chromatography the best option? Int. J. Mol. Sci. 21, 6466.   DOI
71 Fang, Y., Wu, N., Gan, X., Yan, W., Morrell, J.C., and Gould, S.J. (2007). Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol. 5, e158.   DOI
72 Fukuda, S., Kita, S., Obata, Y., Fujishima, Y., Nagao, H., Masuda, S., Tanaka, Y., Nishizawa, H., Funahashi, T., Takagi, J., et al. (2017). The unique prodomain of T-cadherin plays a key role in adiponectin binding with the essential extracellular cadherin repeats 1 and 2. J. Biol. Chem. 292, 7840-7849.   DOI
73 Ghossoub, R., Chery, M., Audebert, S., Leblanc, R., Egea-Jimenez, A.L., Lembo, F., Mammar, S., Le Dez, F., Camoin, L., Borg, J.P., et al. (2020). Tetraspanin-6 negatively regulates exosome production. Proc. Natl. Acad. Sci. U. S. A. 117, 5913-5922.   DOI
74 Henne, W.M., Buchkovich, N.J., and Emr, S.D. (2011). The ESCRT pathway. Dev. Cell 21, 77-91.   DOI
75 van Niel, G., Charrin, S., Simoes, S., Romao, M., Rochin, L., Saftig, P., Marks, M.S., Rubinstein, E., and Raposo, G. (2011). The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev. Cell 21, 708-721.   DOI
76 Thomou, T., Mori, M.A., Dreyfuss, J.M., Konishi, M., Sakaguchi, M., Wolfrum, C., Rao, T.N., Winnay, J.N., Garcia-Martin, R., Grinspoon, S.K., et al. (2017). Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450-455.   DOI
77 Thompson, C.A., Purushothaman, A., Ramani, V.C., Vlodavsky, I., and Sanderson, R.D. (2013). Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J. Biol. Chem. 288, 10093-10099.   DOI
78 Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., Schwille, P., Brugger, B., and Simons, M. (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244-1247.   DOI
79 Tsugawa-Shimizu, Y., Fujishima, Y., Kita, S., Minami, S., Sakaue, T.A., Nakamura, Y., Okita, T., Kawachi, Y., Fukada, S., Namba-Hamano, T., et al. (2021). Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin. Am. J. Physiol. Endocrinol. Metab. 320, E179-E190.   DOI
80 Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J., and Lotvall, J.O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654-659.   DOI
81 Verderio, C., Gabrielli, M., and Giussani, P. (2018). Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles. J. Lipid Res. 59, 1325-1340.   DOI
82 Hitomi, K., Okada, R., Loo, T.M., Miyata, K., Nakamura, A.J., and Takahashi, A. (2020). DNA damage regulates senescence-associated extracellular vesicle release via the ceramide pathway to prevent excessive inflammatory responses. Int. J. Mol. Sci. 21, 3720.   DOI
83 Imjeti, N.S., Menck, K., Egea-Jimenez, A.L., Lecointre, C., Lembo, F., Bouguenina, H., Badache, A., Ghossoub, R., David, G., Roche, S., et al. (2017). Syntenin mediates SRC function in exosomal cell-to-cell communication. Proc. Natl. Acad. Sci. U. S. A. 114, 12495-12500.   DOI
84 Jeppesen, D.K., Fenix, A.M., Franklin, J.L., Higginbotham, J.N., Zhang, Q., Zimmerman, L.J., Liebler, D.C., Ping, J., Liu, Q., Evans, R., et al. (2019). Reassessment of exosome composition. Cell 177, 428-445.e18.   DOI
85 Kajimoto, T., Okada, T., Miya, S., Zhang, L., and Nakamura, S. (2013). Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat. Commun. 4, 2712.   DOI
86 Urbanelli, L., Buratta, S., Sagini, K., Tancini, B., and Emiliani, C. (2016). Extracellular vesicles as new players in cellular senescence. Int. J. Mol. Sci. 17, 1408.   DOI
87 Takasugi, M. (2018). Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 17, e12734.   DOI
88 Thery, C., Amigorena, S., Raposo, G., and Clayton, A. (2006). Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. Chapter 3, Unit 3.22.
89 Tosar, J.P., Witwer, K., and Cayota, A. (2021). Revisiting extracellular RNA release, processing, and function. Trends Biochem. Sci. 46, 438-445.   DOI
90 Fedele, A.O. and Proud, C.G. (2020). Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling. Biosci. Rep. 40, BSR20200905.   DOI
91 Freeman, D.W., Noren Hooten, N., Eitan, E., Green, J., Mode, N.A., Bodogai, M., Zhang, Y., Lehrmann, E., Zonderman, A.B., Biragyn, A., et al. (2018). Altered extracellular vesicle concentration, cargo, and function in diabetes. Diabetes 67, 2377-2388.   DOI
92 Garcia-Martin, R., Wang, G., Brandao, B.B., Zanotto, T.M., Shah, S., Kumar Patel, S., Schilling, B., and Kahn, C.R. (2022). MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 601, 446-451.   DOI
93 Gezsi, A., Kovacs, A., Visnovitz, T., and Buzas, E.I. (2019). Systems biology approaches to investigating the roles of extracellular vesicles in human diseases. Exp. Mol. Med. 51, 1-11.
94 Ghossoub, R., Lembo, F., Rubio, A., Gaillard, C.B., Bouchet, J., Vitale, N., Slavik, J., Machala, M., and Zimmermann, P. (2014). SynteninALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat. Commun. 5, 3477.   DOI
95 Hosen, M.R., Li, Q., Liu, Y., Zietzer, A., Maus, K., Goody, P., Uchida, S., Latz, E., Werner, N., Nickenig, G., et al. (2021). CAD increases the long noncoding RNA PUNISHER in small extracellular vesicles and regulates endothelial cell function via vesicular shuttling. Mol. Ther. Nucleic Acids 25, 388-405.   DOI