Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

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)
  • Received : 2022.07.05
  • Accepted : 2022.08.15
  • Published : 2022.11.30
Download PDF
⟨ Previous Next ⟩

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

References

  1. 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. https://doi.org/10.1016/j.nbd.2011.01.029
  2. Andreu, Z. and Yanez-Mo, M. (2014). Tetraspanins in extracellular vesicle formation and function. Front. Immunol. 5, 442.
  3. 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. https://doi.org/10.1038/ncb2502
  4. 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. https://doi.org/10.1016/j.bbagen.2019.129414
  5. 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. https://doi.org/10.1016/j.bbrc.2011.10.121
  6. Cashikar, A.G. and Hanson, P.I. (2019). A cell-based assay for CD63-containing extracellular vesicles. PLoS One 14, e0220007. https://doi.org/10.1371/journal.pone.0220007
  7. 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. https://doi.org/10.1073/pnas.1808855115
  8. 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. https://doi.org/10.1083/jcb.201002049
  9. 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. https://doi.org/10.1038/s41586-018-0392-8
  10. 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. https://doi.org/10.1242/jcs.259324
  11. 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. https://doi.org/10.1016/S0022-1759(00)00321-5
  12. 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.
  13. 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. https://doi.org/10.1146/annurev-cellbio-101512-122326
  14. 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. https://doi.org/10.1080/15548627.2020.1752548
  15. 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. https://doi.org/10.1016/j.neurobiolaging.2014.02.012
  16. 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. https://doi.org/10.1523/JNEUROSCI.1429-16.2016
  17. 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. https://doi.org/10.1038/s41598-017-01386-z
  18. 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. https://doi.org/10.1016/j.arr.2016.05.001
  19. 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. https://doi.org/10.1038/nrd3978
  20. 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.
  21. 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. https://doi.org/10.1016/j.bbamcr.2009.09.011
  22. 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. https://doi.org/10.1371/journal.pbio.0050158
  23. Fedele, A.O. and Proud, C.G. (2020). Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling. Biosci. Rep. 40, BSR20200905. https://doi.org/10.1042/BSR20200905
  24. 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. https://doi.org/10.2337/db17-1308
  25. 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. https://doi.org/10.1074/jbc.M117.780734
  26. 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. https://doi.org/10.1038/s41586-021-04234-3
  27. 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.
  28. 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. https://doi.org/10.1073/pnas.1922447117
  29. 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. https://doi.org/10.1038/ncomms4477
  30. 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. https://doi.org/10.2147/IJN.S291956
  31. Henne, W.M., Buchkovich, N.J., and Emr, S.D. (2011). The ESCRT pathway. Dev. Cell 21, 77-91. https://doi.org/10.1016/j.devcel.2011.05.015
  32. Hessvik, N.P. and Llorente, A. (2018). Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci. 75, 193-208. https://doi.org/10.1007/s00018-017-2595-9
  33. 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. https://doi.org/10.1038/s41598-018-32535-7
  34. 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. https://doi.org/10.3390/ijms21103720
  35. 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. https://doi.org/10.1016/j.omtn.2021.05.023
  36. Hurley, J.H., Boura, E., Carlson, L.A., and Rozycki, B. (2010). Membrane budding. Cell 143, 875-887. https://doi.org/10.1016/j.cell.2010.11.030
  37. 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. https://doi.org/10.1073/pnas.1713433114
  38. 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. https://doi.org/10.1007/s11010-020-03703-z
  39. 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. https://doi.org/10.1007/s10735-012-9468-1
  40. 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. https://doi.org/10.1016/j.cell.2019.02.029
  41. 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. https://doi.org/10.1126/science.abb5916
  42. 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. https://doi.org/10.1016/j.mam.2017.11.005
  43. 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. https://doi.org/10.1038/ncomms3712
  44. Kalluri, R. and LeBleu, V.S. (2020). The biology, function, and biomedical applications of exosomes. Science 367, eaau6977. https://doi.org/10.1126/science.aau6977
  45. 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. https://doi.org/10.1038/s41598-021-81697-4
  46. 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. https://doi.org/10.1007/s00125-022-05708-3
  47. 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. https://doi.org/10.7554/eLife.48675
  48. 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. https://doi.org/10.1172/JCI129193
  49. Kita, S. and Shimomura, I. (2021). Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes. J. Biochem. 169, 173-179. https://doi.org/10.1093/jb/mvaa105
  50. 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. https://doi.org/10.1038/s41467-018-03733-8
  51. 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. https://doi.org/10.1038/s42003-020-0830-7
  52. 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. https://doi.org/10.1080/20013078.2017.1286095
  53. 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. https://doi.org/10.1038/s41556-018-0250-9
  54. 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. https://doi.org/10.1080/20013078.2019.1696517
  55. 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. https://doi.org/10.1016/j.cell.2015.05.009
  56. 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. https://doi.org/10.1111/ggi.13928
  57. 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. https://doi.org/10.1016/j.cell.2019.02.018
  58. 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. https://doi.org/10.1038/ncb3112
  59. 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. https://doi.org/10.1016/j.ymthe.2020.06.026
  60. 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. https://doi.org/10.1038/s41580-020-0251-y
  61. 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. https://doi.org/10.1172/jci.insight.99680
  62. 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.
  63. 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. https://doi.org/10.1111/febs.12775
  64. 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. https://doi.org/10.1016/j.addr.2021.113872
  65. 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. https://doi.org/10.1038/srep23978
  66. 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. https://doi.org/10.1038/cr.2015.29
  67. 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. https://doi.org/10.1016/j.cellsig.2020.109771
  68. 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. https://doi.org/10.1074/jbc.M301642200
  69. 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.
  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. https://doi.org/10.3390/ijms21186466
  71. Skotland, T., Sandvig, K., and Llorente, A. (2017). Lipids in exosomes: current knowledge and the way forward. Prog. Lipid Res. 66, 30-41. https://doi.org/10.1016/j.plipres.2017.03.001
  72. Stuffers, S., Sem Wegner, C., Stenmark, H., and Brech, A. (2009). Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10, 925-937. https://doi.org/10.1111/j.1600-0854.2009.00920.x
  73. 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. https://doi.org/10.1038/s41598-022-10522-3
  74. 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. https://doi.org/10.1038/s43587-021-00151-2
  75. 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. https://doi.org/10.1038/ncomms15287
  76. Takasugi, M. (2018). Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 17, e12734. https://doi.org/10.1111/acel.12734
  77. 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.
  78. 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. https://doi.org/10.1038/s41598-018-37115-3
  79. 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.
  80. 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. https://doi.org/10.1038/nature21365
  81. 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. https://doi.org/10.1074/jbc.C112.444562
  82. Tosar, J.P., Witwer, K., and Cayota, A. (2021). Revisiting extracellular RNA release, processing, and function. Trends Biochem. Sci. 46, 438-445. https://doi.org/10.1016/j.tibs.2020.12.008
  83. 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. https://doi.org/10.1126/science.1153124
  84. 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. https://doi.org/10.1152/ajpendo.00393.2020
  85. 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. https://doi.org/10.3390/ijms17091408
  86. 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. https://doi.org/10.1038/ncb1596
  87. 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. https://doi.org/10.1016/j.devcel.2011.08.019
  88. 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. https://doi.org/10.1038/nrm.2017.125
  89. 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. https://doi.org/10.1194/jlr.R083915
  90. 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. https://doi.org/10.1038/s41422-020-00409-1
  91. 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.
  92. 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. https://doi.org/10.1080/20013078.2019.1648167
  93. Xie, S., Zhang, Q., and Jiang, L. (2022). Current knowledge on exosome biogenesis, cargo-sorting mechanism and therapeutic implications. Membranes (Basel) 12, 498. https://doi.org/10.3390/membranes12050498
  94. Yao, R.W., Wang, Y., and Chen, L.L. (2019). Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542-551. https://doi.org/10.1038/s41556-019-0311-8
  95. 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. https://doi.org/10.1091/mbc.12.2.339