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Review Article

Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease

ORCID Icon & ORCID Icon
Pages 355-369 | Received 13 Oct 2023, Accepted 22 May 2024, Published online: 04 Jun 2024

References

  • Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966–1986. doi: 10.1097/hep.0000000000000520.
  • Younossi ZM, Golabi P, Paik JM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (Nash): a systematic review. Hepatology. 2023;77(4):1335–1347. doi: 10.1097/hep.0000000000000004.
  • Zhou F, Zhou J, Wang W, et al. Unexpected rapid increase in the burden of NAFLD in China from 2008 to 2018: a systematic review and meta-analysis. Hepatology. 2019;70(4):1119–1133. doi: 10.1002/hep.30702.
  • Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030. J Hepatol. 2018;69(4):896–904. doi: 10.1016/j.jhep.2018.05.036.
  • Farrell GC, Haczeyni F, Chitturi S. Pathogenesis of nash: how metabolic complications of overnutrition favour lipotoxicity and pro-inflammatory fatty liver disease. Adv Exp Med Biol. 2018;1061:19–44. doi: 10.1007/978-981-10-8684-7_3.
  • Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun. 2020;4(4):478–492. doi: 10.1002/hep4.1479.
  • Geng Y, Faber KN, De Meijer VE, et al. How does hepatic lipid accumulation lead to lipotoxicity in non-Alcoholic fatty liver disease? Hepatol Int. 2021;15(1):21–35. doi: 10.1007/s12072-020-10121-2.
  • Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi: 10.1002/hep.28431.
  • Henry L, Paik J, Younossi ZM. Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world. Aliment Pharmacol Ther. 2022;56(6):942–956. doi: 10.1111/apt.17158.
  • Varderidou-Minasian S, Lorenowicz MJ. Mesenchymal stromal/stem cell-derived extracellular vesicles in tissue repair: challenges and opportunities. Theranostics. 2020;10(13):5979–5997. doi: 10.7150/thno.40122.
  • Han C, Yang J, Sun J, et al. Extracellular vesicles in cardiovascular disease: biological functions and therapeutic implications. Pharmacol Ther. 2022;233:108025. doi: 10.1016/j.pharmthera.2021.108025.
  • Newman LA, Muller K, Rowland A. Circulating cell-specific extracellular vesicles as biomarkers for the diagnosis and monitoring of chronic liver diseases. Cell Mol Life Sci. 2022;79(5):232. doi: 10.1007/s00018-022-04256-8.
  • Kalluri R, Lebleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977. doi: 10.1126/science.aau6977.
  • Dilsiz N. Hallmarks of exosomes. Future Sci OA. 2021;8(1):FSO764. doi: 10.2144/fsoa-2021-0102.
  • Vizoso FJ, Eiro N, Cid S, et al. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18(9):1852. doi: 10.3390/ijms18091852.
  • Chen B, Cai J, Wei Y, et al. Exosomes are comparable to source adipose stem cells in fat graft retention with up-regulating early inflammation and angiogenesis. Plast Reconstr Surg. 2019;144(5):816e–827e. doi: 10.1097/PRS.0000000000006175.
  • Ghiasloo M, De Wilde L, Singh K, et al. A systematic review on extracellular vesicles-enriched fat grafting: a shifting paradigm. Aesthet Surg J. 2021;41(11):NP1695–NP1705. doi: 10.1093/asj/sjaa362.
  • Cocozza F, Grisard E, Martin-Jaular L, et al. Snapshot: extracellular vesicles. Cell. 2020;182(1):262–262.e261. doi: 10.1016/j.cell.2020.04.054.
  • Eitan E, Suire C, Zhang S, et al. Impact of lysosome status on extracellular vesicle content and release. Ageing Res Rev. 2016;32:65–74. doi: 10.1016/j.arr.2016.05.001.
  • Szatanek R, Baj-Krzyworzeka M, Zimoch J, et al. The methods of choice for extracellular vesicles (evs) characterization. Int J Mol Sci. 2017;18(6):1153. doi: 10.3390/ijms18061153.
  • Sidhom K, Obi PO, Saleem A. A review of exosomal isolation methods: is size exclusion chromatography the best option? Int J Mol Sci. 2020;21(18):6466. doi: 10.3390/ijms21186466.
  • Thomou T, Mori MA, Dreyfuss JM, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017;542(7642):450–455. doi: 10.1038/nature21365.
  • Zhao H, Shang Q, Pan Z, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes. 2018;67(2):235–247. doi: 10.2337/db17-0356.
  • Lagos-Quintana M, Rauhut R, Lendeckel W, et al. Identification of novel genes coding for small expressed RNAs. Science. 2001;294(5543):853–858. doi: 10.1126/science.1064921.
  • Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in caenorhabditis elegans. Science. 2001;294(5543):858–862. doi: 10.1126/science.1065062.
  • Berezikov E, Guryev V, Van De Belt J, et al. Phylogenetic shadowing and computational identification of human microrna genes. Cell. 2005;120(1):21–24. doi: 10.1016/j.cell.2004.12.031.
  • Mahmoudi A, Butler AE, Jamialahmadi T, et al. The role of exosomal miRNA in nonalcoholic fatty liver disease. J Cellular Physiol. 2022;237(4):2078–2094. doi: 10.1002/jcp.30699.
  • Broermann A, Schmid R, Gabrielyan O, et al. Exosomal miRNAs as potential biomarkers to monitor phosphodiesterase 5 inhibitor ­induced anti-fibrotic effects on Ccl4 treated rats. Int J Mol Sci. 2020;22(1):382. doi: 10.3390/ijms22010382.
  • Hu J, Jiang Y, Wu X, et al. Exosomal mir-17-5p from adipose-derived mesenchymal stem cells inhibits abdominal aortic aneurysm by suppressing Txnip-Nlrp3 inflammasome. Stem Cell Res Ther. 2022;13(1):349. doi: 10.1186/s13287-022-03037-1.
  • Martínez MC, Andriantsitohaina R. Extracellular vesicles in metabolic syndrome. Circ Res. 2017;120(10):1674–1686. doi: 10.1161/circresaha.117.309419.
  • Kariba Y, Yoshizawa T, Sato Y, et al. Brown adipocyte-derived exosomal mir-132-3p suppress hepatic Srebf1 expression and thereby attenuate expression of lipogenic genes. Biochem Biophys Res Commun. 2020;530(3):500–507. doi: 10.1016/j.bbrc.2020.05.090.
  • Jung YJ, Kim HK, Cho Y, et al. Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes. Sci Adv. 2020;6(13):eaay6721. doi: 10.1126/sciadv.aay6721.
  • Watanabe T, Tsuchiya A, Takeuchi S, et al. Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles. Regen Ther. 2020;14:252–261. doi: 10.1016/j.reth.2020.03.012.
  • Mahmood A, Seetharaman R, Kshatriya P, et al. Stem cell transplant for advanced stage liver disorders: current scenario and future prospects. CMC. 2020;27(37):6276–6293. doi: 10.2174/0929867326666191004161802.
  • Mathieu M, Martin-Jaular L, Lavieu G, et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21(1):9–17. doi: 10.1038/s41556-018-0250-9.
  • Couch Y, Buzas EI, Di Vizio D, et al. A brief history of nearly Ev-Erything - the rise and rise of extracellular vesicles. J Extracell Vesicles. 2021;10(14):e12144. doi: 10.1002/jev2.12144.
  • Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–579. doi: 10.1038/nri855.
  • Chen Y, Zhao Y, Yin Y, et al. Mechanism of cargo sorting into small extracellular vesicles. Bioengineered. 2021;12(1):8186–8201. doi: 10.1080/21655979.2021.1977767.
  • Brennan K, Martin K, Fitzgerald SP, et al. A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Sci Rep. 2020;10(1):1039. doi: 10.1038/s41598-020-57497-7.
  • Gardiner C, Di Vizio D, Sahoo S, et al. Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey. J Extracell Vesicles. 2016;5(1):32945. doi: 10.3402/jev.v5.32945.
  • Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (Misev2018): a position statement of the international society for extracellular vesicles and update of the Misev2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750. doi: 10.1080/20013078.2018.1535750.
  • Royo F, Théry C, Falcón-Pérez JM, et al. Methods for separation and characterization of extracellular vesicles: results of a worldwide survey performed by the isev rigor and standardization subcommittee. Cells. 2020;9(9):1955. doi: 10.3390/cells9091955.
  • Wang JM, Li YJ, Wu JY, et al. Comparative evaluation of methods for isolating small extracellular vesicles derived from pancreatic cancer cells. Cell Biosci. 2021;11(1):37. doi: 10.1186/s13578-021-00550-3.
  • Linares R, Tan S, Gounou C, et al. High-speed centrifugation induces aggregation of extracellular vesicles. J Extracell Vesicles. 2015;4(1):29509. doi: 10.3402/jev.v4.29509.
  • Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles. 2015;4(1):27031. doi: 10.3402/jev.v4.27031.
  • Yang J, Gao X, Xing X, et al. An isolation system to collect high quality and purity extracellular vesicles from serum. Int J Nanomedicine. 2021;16:6681–6692. doi: 10.2147/IJN.S328325.
  • Baranyai T, Herczeg K, Onódi Z, et al. Isolation of exosomes from blood plasma: qualitative and quantitative comparison of ultracentrifugation and size exclusion chromatography methods. PLoS One. 2015;10(12):e0145686. doi: 10.1371/journal.pone.0145686.
  • Wei R, Zhao L, Kong G, et al. Combination of size-exclusion chromatography and ultracentrifugation improves the proteomic profiling of plasma-derived small extracellular vesicles. Biol Proced Online. 2020;22(1):12. doi: 10.1186/s12575-020-00125-5.
  • Huang K, Garimella S, Clay-Gilmour A, et al. Comparison of human urinary exosomes isolated via ultracentrifugation alone versus ultracentrifugation followed by sec column-purification. J Pers Med. 2022;12(3):340. doi: 10.3390/jpm12030340.
  • Mousavi SM, Amin Mahdian SM, Ebrahimi MS, et al. Microfluidics for detection of exosomes and microRNAs in cancer: state of the art. Mol Ther Nucleic Acids. 2022;28:758–791. doi: 10.1016/j.omtn.2022.04.011.
  • Zhang H, Freitas D, Kim HS, et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol. 2018;20(3):332–343. doi: 10.1038/s41556-018-0040-4.
  • Filipe V, Hawe A, Jiskoot W. Critical evaluation of nanoparticle tracking analysis (NTA) by nanosight for the measurement of nanoparticles and protein aggregates. Pharm Res. 2010;27(5):796–810. doi: 10.1007/s11095-010-0073-2.
  • Dragovic RA, Gardiner C, Brooks AS, et al. Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomedicine. 2011;7(6):780–788. doi: 10.1016/j.nano.2011.04.003.
  • Akers JC, Ramakrishnan V, Nolan JP, et al. Comparative analysis of technologies for quantifying extracellular vesicles (EVS) in clinical cerebrospinal fluids (CSF). PLoS One. 2016;11(2):e0149866. doi: 10.1371/journal.pone.0149866.
  • Zhang Y, Bi J, Huang J, et al. Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 2020;15:6917–6934. doi: 10.2147/IJN.S264498.
  • Liu X, Zong Z, Xing M, et al. pH-mediated clustering of exosomes: breaking through the size limit of exosome analysis in conventional flow cytometry. Nano Lett. 2021;21(20):8817–8823. doi: 10.1021/acs.nanolett.1c03211.
  • Van Der Pol E, Coumans FA, Grootemaat AE, et al. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost. 2014;12(7):1182–1192. doi: 10.1111/jth.12602.
  • Trajkovic K, Hsu C, Chiantia S, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–1247. doi: 10.1126/science.1153124.
  • Nakao Y, Amrollahi P, Parthasarathy G, et al. Circulating extracellular vesicles are a biomarker for NAFLD resolution and response to weight loss surgery. Nanomedicine. 2021;36:102430. doi: 10.1016/j.nano.2021.102430.
  • Landa S, Verlov N, Fedorova N, et al. Extracellular particles as carriers of cholesterol not associated with lipoproteins. Membranes (Basel). 2022;12(6):618. doi: 10.3390/membranes12060618.
  • Wang W, Zhu N, Yan T, et al. The crosstalk: exosomes and lipid metabolism. Cell Commun Signal. 2020;18(1):119. doi: 10.1186/s12964-020-00581-2.
  • Zhao Z, Zhong L, Li P, et al. Cholesterol impairs hepatocyte lysosomal function causing M1 polarization of macrophages via exosomal mir-122-5p. Exp Cell Res. 2020;387(1):111738. doi: 10.1016/j.yexcr.2019.111738.
  • Abdullah M, Nakamura T, Ferdous T, et al. Cholesterol regulates exosome release in cultured astrocytes. Front Immunol. 2021;12:722581. doi: 10.3389/fimmu.2021.722581.
  • Zhao Y, Zhao MF, Jiang S, et al. Liver governs adipose remodelling via extracellular vesicles in response to lipid overload. Nat Commun. 2020;11(1):719. doi: 10.1038/s41467-020-14450-6.
  • Yang L, Wang T, Zhang X, et al. Exosomes derived from human placental mesenchymal stem cells ameliorate myocardial infarction via anti-inflammation and restoring gut dysbiosis. BMC Cardiovasc Disord. 2022;22(1):61. doi: 10.1186/s12872-022-02508-w.
  • Fujita K, Somiya M, Kuroda S, et al. Induction of lipid droplets in non-macrophage cells as well as macrophages by liposomes and exosomes. Biochem Biophys Res Commun. 2019;510(1):184–190. doi: 10.1016/j.bbrc.2019.01.078.
  • Povero D, Eguchi A, Li H, et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One. 2014;9(12):e113651. doi: 10.1371/journal.pone.0113651.
  • Kakazu E, Mauer AS, Yin M, et al. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an Ire1alpha-dependent manner. J Lipid Res. 2016;57(2):233–245. doi: 10.1194/jlr.M063412.
  • Li J, Liu H, Mauer AS, et al. Characterization of cellular sources and circulating levels of extracellular vesicles in a dietary murine model of nonalcoholic steatohepatitis. Hepatol Commun. 2019;3(9):1235–1249. doi: 10.1002/hep4.1404.
  • Zhang J, Tan J, Wang M, et al. Lipid-induced dram recruits stom to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD. Sci Adv. 2021;7(45):eabh1541. doi: 10.1126/sciadv.abh1541.
  • Povero D, Eguchi A, Niesman IR, et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require vanin-1 for uptake by endothelial cells. Sci Signal. 2013;6(296):ra88. doi: 10.1126/scisignal.2004512.
  • Povero D, Yamashita H, Ren W, et al. Characterization and proteome of circulating extracellular vesicles as potential biomarkers for nash. Hepatol Commun. 2020;4(9):1263–1278. doi: 10.1002/hep4.1556.
  • Kornek M, Lynch M, Mehta SH, et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology. 2012;143(2):448–458. doi: 10.1053/j.gastro.2012.04.031.
  • Welsh JA, Scorletti E, Clough GF, et al. Leukocyte extracellular vesicle concentration is inversely associated with liver fibrosis severity in NAFLD. J Leukoc Biol. 2018;104(3):631–639. doi: 10.1002/JLB.5A1217-501R.
  • Hirsova P, Ibrahim SH, Krishnan A, et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology. 2016;150(4):956–967. doi: 10.1053/j.gastro.2015.12.037.
  • Ostrowski M, Carmo NB, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30. doi: 10.1038/ncb2000.
  • Liao CY, Song MJ, Gao Y, et al. Hepatocyte-derived lipotoxic extracellular vesicle sphingosine 1-phosphate induces macrophage chemotaxis. Front Immunol. 2018;9:2980. doi: 10.3389/fimmu.2018.02980.
  • Dasgupta D, Nakao Y, Mauer AS, et al. Ire1a stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology. 2020;159(4):1487–1503.e1417. doi: 10.1053/j.gastro.2020.06.031.
  • Fukushima M, Dasgupta D, Mauer AS, et al. Star-related lipid transfer domain 11 (Stard11)-mediated ceramide transport mediates extracellular vesicle biogenesis. J Biol Chem. 2018;293(39):15277–15289. doi: 10.1074/jbc.RA118.002587.
  • Mauer AS, Hirsova P, Maiers JL, et al. Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2017;312(3):G300–G313. doi: 10.1152/ajpgi.00222.2016.
  • Zhang X, Shen J, Man K, et al. Cxcl10 plays a key role as an inflammatory mediator and a non-Invasive biomarker of non-alcoholic steatohepatitis. J Hepatol. 2014;61(6):1365–1375. doi: 10.1016/j.jhep.2014.07.006.
  • Ibrahim SH, Hirsova P, Tomita K, et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology. 2016;63(3):731–744. doi: 10.1002/hep.28252.
  • Tomita K, Freeman BL, Bronk SF, et al. Cxcl10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep. 2016;6(1):28786. doi: 10.1038/srep28786.
  • Tomita K, Kabashima A, Freeman BL, et al. Mixed lineage kinase 3 mediates the induction of Cxcl10 by a Stat1-dependent mechanism during hepatocyte lipotoxicity. J Cellular Biochem. 2017;118(10):3249–3259. doi: 10.1002/jcb.25973.
  • Ibrahim SH, Gores GJ, Hirsova P, et al. Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. Liver Int. 2014;34(3):427–437. doi: 10.1111/liv.12353.
  • Nojima H, Konishi T, Freeman CM, et al. Chemokine receptors, Cxcr1 and Cxcr2, differentially regulate exosome release in hepatocytes. PLoS One. 2016;11(8):e0161443. doi: 10.1371/journal.pone.0161443.
  • Dhayni K, Zibara K, Issa H, et al. Targeting Cxcr1 and Cxcr2 receptors in cardiovascular diseases. Pharmacol Ther. 2022;237:108257. doi: 10.1016/j.pharmthera.2022.108257.
  • Qureshi K, Abrams GA. Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2007;13(26):3540–3553. doi: 10.3748/wjg.v13.i26.3540.
  • Duan Y, Pan X, Luo J, et al. Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front Immunol. 2022;13:880298. doi: 10.3389/fimmu.2022.880298.
  • Lee EY, Lee ZH, Song YW. Cxcl10 and autoimmune diseases. Autoimmun Rev. 2009;8(5):379–383. doi: 10.1016/j.autrev.2008.12.002.
  • Cannito S, Morello E, Bocca C, et al. Microvesicles released from fat-laden cells promote activation of hepatocellular Nlrp3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PLoS One. 2017;12(3):e0172575. doi: 10.1371/journal.pone.0172575.
  • Guo Q, Furuta K, Lucien F, et al. Integrin beta1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine nash. J Hepatol. 2019;71(6):1193–1205. doi: 10.1016/j.jhep.2019.07.019.
  • Garcia-Martinez I, Santoro N, Chen Y, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of Tlr9. J Clin Invest. 2016;126(3):859–864. doi: 10.1172/JCI83885.
  • Hernández A, Geng Y, Sepúlveda R, et al. Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with kupffer cells through extracellular vesicles. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165753. doi: 10.1016/j.bbadis.2020.165753.
  • Hernández A, Reyes D, Geng Y, et al. Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells. Biochim Biophys Acta Mol Basis Dis. 2020;1866(10):165857. doi: 10.1016/j.bbadis.2020.165857.
  • Gim JA, Bang SM, Lee YS, et al. Evaluation of the severity of nonalcoholic fatty liver disease through analysis of serum exosomal mirna expression. PLoS One. 2021;16(8):e0255822. doi: 10.1371/journal.pone.0255822.
  • López-Pastor AR, Infante-Menéndez J, González-Illanes T, et al. Concerted regulation of non-alcoholic fatty liver disease progression by microRNAs in apolipoprotein E-deficient mice. Dis Model Mech. 2021;14(12):dmm049173. doi: 10.1242/dmm.049173.
  • Newman LA, Useckaite Z, Johnson J, et al. Selective isolation of liver-derived extracellular vesicles redefines performance of mirna biomarkers for non-alcoholic fatty liver disease. Biomedicines. 2022;10(1):195. doi: 10.3390/biomedicines10010195.
  • Zhang JW, Pan HT. Microrna profiles of serum exosomes derived from children with nonalcoholic fatty liver. Genes Genomics. 2022;44(7):879–888. doi: 10.1007/s13258-021-01150-8.
  • Jiang H, Qian Y, Shen Z, et al. Circulating microRNA135a3p in serum extracellular vesicles as a potential biological marker of nonalcoholic fatty liver disease. Mol Med Rep. 2021;24(1):498. doi: 10.3892/mmr.2021.12137.
  • Cermelli S, Ruggieri A, Marrero JA, et al. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6(8):e23937. doi: 10.1371/journal.pone.0023937.
  • Pirola CJ, Gianotti TF, Castaño GO, et al. Circulating microRNA-122 signature in nonalcoholic fatty liver disease and cardiovascular disease: a new endocrine system in metabolic syndrome. Hepatology. 2013;57(6):2545–2547. doi: 10.1002/hep.26116.
  • Csak T, Bala S, Lippai D, et al. MicroRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int. 2015;35(2):532–541. doi: 10.1111/liv.12633.
  • Liu XL, Pan Q, Cao HX, et al. Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through rictor/AKT/forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease. Hepatology. 2020;72(2):454–469. doi: 10.1002/hep.31050.
  • Liu H, Niu Q, Wang T, et al. Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages. Int J Biol Sci. 2021;17(14):3745–3759. doi: 10.7150/ijbs.57610.
  • Koenen MT, Brandt EF, Kaczor DM, et al. Extracellular vesicles from steatotic hepatocytes provoke pro-fibrotic responses in cultured stellate cells. Biomolecules. 2022;12(5):698. doi: 10.3390/biom12050698.
  • Povero D, Panera N, Eguchi A, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-gamma. Cell Mol Gastroenterol Hepatol. 2015;1(6):646–663.e644. doi: 10.1016/j.jcmgh.2015.07.007.
  • Lee YS, Kim SY, Ko E, et al. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep. 2017;7(1):3710. doi: 10.1038/s41598-017-03389-2.
  • Gao H, Jin Z, Bandyopadhyay G, et al. Mir-690 treatment causes decreased fibrosis and steatosis and restores specific kupffer cell functions in nash. Cell Metab. 2022;34(7):978–990.e974. doi: 10.1016/j.cmet.2022.05.008.
  • Hou X, Yin S, Ren R, et al. Myeloid-cell-specific Il-6 signaling promotes microRNA-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology. 2021;74(1):116–132. doi: 10.1002/hep.31658.
  • He Y, Hwang S, Cai Y, et al. MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology. 2019;70(4):1150–1167. doi: 10.1002/hep.30645.
  • He Y, Rodrigues RM, Wang X, et al. Neutrophil-to-hepatocyte communication via LDLR-dependent mir-223-enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis. J Clin Invest. 2021;131(3):e141513. doi: 10.1172/JCI141513.
  • Calvente CJ, Tameda M, Johnson CD, et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest. 2019;129(10):4091–4109. doi: 10.1172/JCI122258.
  • He Y, Feng D, Li M, et al. Hepatic mitochondrial DNA/toll-like receptor 9/microRNA-223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice. Hepatology. 2017;66(1):220–234. doi: 10.1002/hep.29153.
  • Duval C, Thissen U, Keshtkar S, et al. Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57bl/6 mice. Diabetes. 2010;59(12):3181–3191. doi: 10.2337/db10-0224.
  • Flaherty SE, 3rd, Grijalva A, Xu X, et al. A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science. 2019;363(6430):989–993. doi: 10.1126/science.aaw2586.
  • Castaño C, Kalko S, Novials A, et al. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci U S A. 2018;115(48):12158–12163. doi: 10.1073/pnas.1808855115.
  • Gu H, Yang K, Shen Z, et al. Er stress-induced adipocytes secrete-aldo-keto reductase 1b7-containing exosomes that cause nonalcoholic steatohepatitis in mice. Free Radic Biol Med. 2021;163:220–233. doi: 10.1016/j.freeradbiomed.2020.12.011.
  • Yan C, Tian X, Li J, et al. A high-fat diet attenuates AMPK Alpha1 in adipocytes to induce exosome shedding and nonalcoholic fatty liver development in vivo. Diabetes. 2021;70(2):577–588. doi: 10.2337/db20-0146.
  • Larter CZ, Yeh MM, Van Rooyen DM, et al. Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. J Gastroenterol Hepatol. 2009;24(10):1658–1668. doi: 10.1111/j.1440-1746.2009.05996.x.
  • Li Y, Luan Y, Li J, et al. Exosomal mir-199a-5p promotes hepatic lipid accumulation by modulating Mst1 expression and fatty acid metabolism. Hepatol Int. 2020;14(6):1057–1074. doi: 10.1007/s12072-020-10096-0.
  • Gu N, You L, Shi C, et al. Expression of mir-199a-3p in human adipocytes is regulated by free fatty acids and adipokines. Mol Med Rep. 2016;14(2):1180–1186. doi: 10.3892/mmr.2016.5379.
  • Czech MP. Mechanisms of insulin resistance related to white, beige, and brown adipocytes. Mol Metab. 2020;34:27–42. doi: 10.1016/j.molmet.2019.12.014.
  • Zhang X, Ji X, Wang Q, et al. New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Protein Cell. 2018;9(2):164–177. doi: 10.1007/s13238-017-0436-0.
  • Du Plessis J, Van Pelt J, Korf H, et al. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology. 2015;149(3):635–648.e614. doi: 10.1053/j.gastro.2015.05.044.
  • Koeck ES, Iordanskaia T, Sevilla S, et al. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease. J Surg Res. 2014;192(2):268–275. doi: 10.1016/j.jss.2014.06.050.
  • Ferrante SC, Nadler EP, Pillai DK, et al. Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease. Pediatr Res. 2015;77(3):447–454. doi: 10.1038/pr.2014.202.
  • Zhao J, Hu L, Gui W, et al. Hepatocyte TGF-beta signaling inhibiting wat browning to promote NAFLD and obesity is associated with let-7b-5p. Hepatol Commun. 2022;6(6):1301–1321. doi: 10.1002/hep4.1892.
  • Shang Q, Bai Y, Wang G, et al. Delivery of adipose-derived stem cells attenuates adipose tissue inflammation and insulin resistance in obese mice through remodeling macrophage phenotypes. Stem Cells Dev. 2015;24(17):2052–2064. doi: 10.1089/scd.2014.0557.
  • He Q, Wang L, Zhao R, et al. Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy. Stem Cell Res Ther. 2020;11(1):223. doi: 10.1186/s13287-020-01731-6.
  • Hyvärinen K, Holopainen M, Skirdenko V, et al. Mesenchymal stromal cells and their extracellular vesicles enhance the anti-inflammatory phenotype of regulatory macrophages by downregulating the production of interleukin (Il)-23 and Il-22. Front Immunol. 2018;9:771. doi: 10.3389/fimmu.2018.00771.
  • Bruno S, Pasquino C, Herrera Sanchez MB, et al. HLSC-derived extracellular vesicles attenuate liver fibrosis and inflammation in a murine model of non-alcoholic steatohepatitis. Mol Ther. 2020;28(2):479–489. doi: 10.1016/j.ymthe.2019.10.016.
  • Cheng L, Yu P, Li F, et al. Human umbilical cord-derived mesenchymal stem cell-exosomal mir-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression. Hum Cell. 2021;34(6):1697–1708. doi: 10.1007/s13577-021-00593-1.
  • Tan Y, Huang Y, Mei R, et al. Hucmsc-derived exosomes delivered Becn1 induces ferroptosis of hepatic stellate cells via regulating the Xct/Gpx4 axis. Cell Death Dis. 2022;13(4):319. doi: 10.1038/s41419-022-04764-2.
  • El-Derany MO, Abdelhamid SG. Upregulation of mir-96-5p by bone marrow mesenchymal stem cells and their exosomes alleviate non-alcoholic steatohepatitis: emphasis on caspase-2 signaling inhibition. Biochem Pharmacol. 2021;190:114624. doi: 10.1016/j.bcp.2021.114624.
  • Zhang Q, Liu X, Piao C, et al. Effect of conditioned medium from adipose derived mesenchymal stem cells on endoplasmic reticulum stress and lipid metabolism after hepatic ischemia reperfusion injury and hepatectomy in swine. Life Sci. 2022;289:120212. doi: 10.1016/j.lfs.2021.120212.
  • Shuen TWH, Alunni-Fabbroni M, Öcal E, et al. Extracellular vesicles may predict response to radioembolization and sorafenib treatment in advanced hepatocellular carcinoma: an exploratory analysis from the soramic trial. Clin Cancer Res. 2022;28(17):3890–3901. doi: 10.1158/1078-0432.Ccr-22-0569.
  • Zuo R, Ye LF, Huang Y, et al. Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7. J Nanobiotechnol. 2021;19(1):396. doi: 10.1186/s12951-021-01137-3.
  • Jiang F, Chen Q, Wang W, et al. Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1. J Hepatol. 2020;72(1):156–166. doi: 10.1016/j.jhep.2019.09.014.
  • Sengupta V, Sengupta S, Lazo A, et al. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe covid-19. Stem Cells Dev. 2020;29(12):747–754. doi: 10.1089/scd.2020.0080.
  • Fuhrmann G, Herrmann IK, Stevens MM. Cell-derived vesicles for drug therapy and diagnostics: opportunities and challenges. Nano Today. 2015;10(3):397–409. doi: 10.1016/j.nantod.2015.04.004.