Exosomes As Mediators and Biomarkers in Fibrosis

References

• Stoorvogel W , KleijmeerMJ, GeuzeHJ, RaposoG. The biogenesis and functions of exosomes. Traffic3(5), 321–330 (2002).
   PubMed Web of Science ®Google Scholar
• Thery C , ZitvogelL, AmigorenaS. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol.2(8), 569–579 (2002).
   PubMed Web of Science ®Google Scholar
• Caby MP , LankarD, Vincendeau-ScherrerC, RaposoG, BonnerotC. Exosomal-like vesicles are present in human blood plasma. Int. Immunol.17(7), 879–887 (2005).
   PubMed Web of Science ®Google Scholar
• Pisitkun T , ShenRF, KnepperMA. Identification and proteomic profiling of exosomes in human urine. Proc. Natl Acad. Sci. USA101(36), 13368–13373 (2004).
   PubMed Web of Science ®Google Scholar
• Njock MS , GuiotJ, HenketMAet al. Sputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis. Thorax74(3), 309–312 (2019).
   PubMed Web of Science ®Google Scholar
• Admyre C , GrunewaldJ, ThybergJet al. Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur. Respir. J.22(4), 578–583 (2003).
   PubMed Web of Science ®Google Scholar
• Yanez-Mo M , SiljanderPR, AndreuZet al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles4, 27066 (2015).
   PubMed Web of Science ®Google Scholar
• Zeisberg M , KalluriR. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol.304(3), C216–C225 (2013).
   PubMed Web of Science ®Google Scholar
• Akhurst RJ , HataA. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov.11(10), 790–811 (2012).
   PubMed Web of Science ®Google Scholar
• Leask A , AbrahamDJ. TGF-β signaling and the fibrotic response. FASEB J.18(7), 816–827 (2004).
   PubMed Web of Science ®Google Scholar
• Hirsova P , GoresGJ. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell. Mol. Gastroenterol. Hepatol.1(1), 17–27 (2015).
   PubMedGoogle Scholar
• Zhang W , ZhouX, ZhangH, YaoQ, LiuY, DongZ. Extracellular vesicles in diagnosis and therapy of kidney diseases. Am. J. Physiol. Renal Physiol.311(5), F844–f851 (2016).
   PubMed Web of Science ®Google Scholar
• Szabo G , Momen-HeraviF. Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat. Rev. Gastroenterol. Hepatol.14(8), 455–466 (2017).
   PubMed Web of Science ®Google Scholar
• Vanhaverbeke M , GalD, HolvoetP. Functional role of cardiovascular exosomes in myocardial injury and atherosclerosis. Adv. Exp. Med. Biol.998, 45–58 (2017).
   PubMed Web of Science ®Google Scholar
• Kubo H . Extracellular vesicles in lung disease. Chest153(1), 210–216 (2018).
   PubMed Web of Science ®Google Scholar
• Martin-Medina A , LehmannM, BurgyO, HermannS, BaarsmaHA, WagnerDE. Increased extracellular vesicles mediate WNT-5A signaling in idiopathic pulmonary fibrosis. doi:10.1164/rccm.201708-1580OC (2018) ( Epub ahead of print).
   Google Scholar
• Stolzenburg LR , HarrisA. Microvesicle-mediated delivery of miR-1343: impact on markers of fibrosis. Cell Tissue Res.371(2), 325–338 (2018).
   PubMed Web of Science ®Google Scholar
• Makiguchi T , YamadaM, YoshiokaYet al. Serum extracellular vesicular miR-21-5p is a predictor of the prognosis in idiopathic pulmonary fibrosis. Respir. Res.17(1), 110 (2016).
   PubMed Web of Science ®Google Scholar
• Liu B , JiangT, HuXet al. Downregulation of microRNA30a in bronchoalveolar lavage fluid from idiopathic pulmonary fibrosis patients. Mol. Med. Rep.18(6), 5799–5806 (2018).
   PubMed Web of Science ®Google Scholar
• Datta R , BansalT, RanaSet al. Myocyte-derived Hsp90 modulates collagen upregulation via biphasic activation of STAT-3 in fibroblasts during cardiac hypertrophy. Mol. Cell. Biol.37(6), e00611-16 (2017).
   PubMed Web of Science ®Google Scholar
• Wang X , GuH, HuangWet al. Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice. Diabetes65(10), 3111–3128 (2016).
   PubMed Web of Science ®Google Scholar
• Feng Y , HuangW, WaniM, YuX, AshrafM. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS ONE9(2), e88685 (2014).
   PubMed Web of Science ®Google Scholar
• Shao L , ZhangY, LanBet al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed. Res. Int.2017, 4150705 (2017).
   PubMed Web of Science ®Google Scholar
• Yamaguchi T , IzumiY, NakamuraYet al. Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. Int. J. Cardiol.178, 239–246 (2015).
   PubMed Web of Science ®Google Scholar
• Khan M , NickoloffE, AbramovaTet al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ. Res.117(1), 52–64 (2015).
   PubMed Web of Science ®Google Scholar
• Chaturvedi P , KalaniA, MedinaI, FamiltsevaA, TyagiSC. Cardiosome mediated regulation of MMP9 in diabetic heart: role of mir29b and mir455 in exercise. J. Cell. Mol. Med.19(9), 2153–2161 (2015).
   PubMed Web of Science ®Google Scholar
• Wang L , LiuJ, XuB, LiuYL, LiuZ. Reduced exosome miR-425 and miR-744 in the plasma represents the progression of fibrosis and heart failure. Kaohsiung J. Med. Sci.34(11), 626–633 (2018).
   PubMed Web of Science ®Google Scholar
• Lv LL , CaoYH, PanMMet al. CD2AP mRNA in urinary exosome as biomarker of kidney disease. Clin. Chim. Acta428, 26–31 (2014).
   PubMed Web of Science ®Google Scholar
• Wu XM , GaoYB, CuiFQ, ZhangN. Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis. Biol. Open5(4), 484–491 (2016).
   PubMed Web of Science ®Google Scholar
• Zhou Y , XiongM, FangLet al. miR-21-containing microvesicles from injured tubular epithelial cells promote tubular phenotype transition by targeting PTEN protein. Am. J. Pathol.183(4), 1183–1196 (2013).
   PubMed Web of Science ®Google Scholar
• Lv CY , DingWJ, WangYLet al. A PEG-based method for the isolation of urinary exosomes and its application in renal fibrosis diagnostics using cargo miR-29c and miR-21 analysis. Int. Urol. Nephrol.50(5), 973–982 (2018).
   PubMed Web of Science ®Google Scholar
• Zhou Y , XiongM, NiuJet al. Secreted fibroblast-derived miR-34a induces tubular cell apoptosis in fibrotic kidney. J. Cell Sci.127(Pt 20), 4494–4506 (2014).
   PubMed Web of Science ®Google Scholar
• Wang B , YaoK, HuuskesBMet al. Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis. Mol. Ther.24(7), 1290–1301 (2016).
   PubMed Web of Science ®Google Scholar
• Zhang A , LiM, WangB, KleinJD, PriceSR, WangXH. miRNA-23a/27a attenuates muscle atrophy and renal fibrosis through muscle-kidney crosstalk. J. Cachexia Sarcopenia Muscle9(4), 755–770 (2018).
   PubMed Web of Science ®Google Scholar
• Zhou Y , FangL, YuYet al. Erythropoietin protects the tubular basement membrane by promoting the bone marrow to release extracellular vesicles containing tPA-targeting miR-144. Am. J. Physiol. Renal Physiol.310(1), F27–40 (2016).
   PubMed Web of Science ®Google Scholar
• Mohan A , SinghRS, KumariMet al. Urinary exosomal microRNA-451-5p is a potential early biomarker of diabetic nephropathy in rats. PLoS ONE11(4), e0154055 (2016).
   PubMed Web of Science ®Google Scholar
• Lv LL , CaoYH, NiHFet al. MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis. Am. J. Physiol. Renal Physiol.305(8), F1220–F1227 (2013).
   PubMed Web of Science ®Google Scholar
• Sole C , Cortes-HernandezJ, FelipML, VidalM, Ordi-RosJ. miR-29c in urinary exosomes as predictor of early renal fibrosis in lupus nephritis. Nephrol. Dial. Transplant.30(9), 1488–1496 (2015).
   PubMed Web of Science ®Google Scholar
• Yu Y , BaiF, QinNet al. Non-proximal renal tubule-derived urinary exosomal miR-200b as a biomarker of renal fibrosis. Nephron139(3), 269–282 (2018).
   PubMed Web of Science ®Google Scholar
• Wang R , DingQ, YaqoobUet al. Exosome adherence and internalization by hepatic stellate cells triggers sphingosine 1-phosphate-dependent migration. J. Biol. Chem.290(52), 30684–30696 (2015).
   PubMed Web of Science ®Google Scholar
• Charrier A , ChenR, ChenLet al. Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver. Surgery156(3), 548–555 (2014).
   PubMed Web of Science ®Google Scholar
• Chen L , ChenR, KemperS, CharrierA, BrigstockDR. Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: role of exosomes in horizontal transfer of Twist1. Am. J. Physiol. Gastrointest. Liver Physiol.309(6), G491–G499 (2015).
   PubMed Web of Science ®Google Scholar
• Chen L , CharrierA, ZhouYet al. Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology59(3), 1118–1129 (2014).
   PubMed Web of Science ®Google Scholar
• Chen L , ChenR, VelazquezVM, BrigstockDR. Fibrogenic signaling is suppressed in hepatic stellate cells through targeting of connective tissue growth factor (CCN2) by cellular or exosomal microRNA-199a-5p. Am. J. Pathol.186(11), 2921–2933 (2016).
   PubMed Web of Science ®Google Scholar
• Qu Y , ZhangQ, CaiXet al. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J. Cell. Mol. Med.21(10), 2491–2502 (2017).
   PubMed Web of Science ®Google Scholar
• Lee YS , KimSY. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci. Rep.7(1), 3710 (2017).
   PubMedGoogle Scholar
• Devhare PB , SasakiR, ShrivastavaS, DiBisceglie AM, RayR, RayRB. Exosome-mediated intercellular communication between Hepatitis C virus-infected hepatocytes and hepatic stellate cells. J. Virol.91(6), pii:e02225–16 (2017).
   Web of Science ®Google Scholar
• Hyun J , WangS, KimJ, KimGJ, JungY. MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells. Sci. Rep.5, 14135 (2015).
   PubMed Web of Science ®Google Scholar
• Lou G , YangY, LiuFet al. MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J. Cell. Mol. Med.21(11), 2963–2973 (2017).
   PubMed Web of Science ®Google Scholar
• Chen L , ChenR, KemperS, CongM, YouH, BrigstockDR. Therapeutic effects of serum extracellular vesicles in liver fibrosis. J. Extracell. Vesicles7(1), 1461505 (2018).
   PubMed Web of Science ®Google Scholar
• Chen J , YuY, LiSet al. MicroRNA-30a ameliorates hepatic fibrosis by inhibiting Beclin1-mediated autophagy. J. Cell. Mol. Med.21(12), 3679–3692 (2017).
   PubMed Web of Science ®Google Scholar
• Zanotti S , GibertiniS, BlasevichFet al. Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis. Matrix Biol.74, 77–100 (2018).
   PubMed Web of Science ®Google Scholar
• De Jong OG , Van BalkomBW, GremmelsH, VerhaarMC. Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2. J. Cell. Mol. Med.20(2), 342–350 (2016).
   PubMed Web of Science ®Google Scholar
• Hu Y , RaoSS, WangZXet al. Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics8(1), 169–184 (2018).
   PubMed Web of Science ®Google Scholar
• Fang S , XuC, ZhangYet al. Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β/SMAD2 pathway during wound healing. Stem Cells Transl. Med.5(10), 1425–1439 (2016).
   PubMed Web of Science ®Google Scholar
• Todd NW , LuzinaIG, AtamasSP. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair5(1), 11 (2012).
   PubMedGoogle Scholar
• Borges FT , MeloSA, OzdemirBCet al. TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J. Am. Soc. Nephrol.24(3), 385–392 (2013).
   PubMed Web of Science ®Google Scholar
• Vuga LJ , Ben-YehudahA, Kovkarova-NaumovskiEet al. WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. Am. J. Respir. Cell Mol. Biol.41(5), 583–589 (2009).
   PubMed Web of Science ®Google Scholar
• Newman DR , SillsWS, HanrahanKet al. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-β and WNT7B in human lung fibroblasts. J. Histochem. Cytochem.64(2), 99–111 (2016).
   PubMed Web of Science ®Google Scholar
• Gross JC , ChaudharyV, BartschererK, BoutrosM. Active Wnt proteins are secreted on exosomes. Nat. Cell. Biol.14(10), 1036–1045 (2012).
   PubMed Web of Science ®Google Scholar
• Tan JL , LauSN, LeawB, NguyenHPT, SalamonsenLA, SaadMI. Amnion epithelial cell-derived exosomes restrict lung injury and enhance endogenous lung repair. Stem Cells Transl. Med.7(2), 180–196 (2018).
   PubMed Web of Science ®Google Scholar
• Stolzenburg LR , WachtelS, DangH, HarrisA. miR-1343 attenuates pathways of fibrosis by targeting the TGF-β receptors. Biochem. J.473(3), 245–256 (2016).
   PubMed Web of Science ®Google Scholar
• Shentu TP , HuangTS, Cernelc-KohanMet al. Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation. Sci. Rep.7(1), 18052 (2017).
   PubMedGoogle Scholar
• Choi M , BanT, RhimT. Therapeutic use of stem cell transplantation for cell replacement or cytoprotective effect of microvesicle released from mesenchymal stem cell. Mol. Cells37(2), 133–139 (2014).
   PubMed Web of Science ®Google Scholar
• Frangogiannis NG . Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol. Aspects Med.65, 70–99 (2019).
   PubMed Web of Science ®Google Scholar
• Kakkar R , LeeRT. Intramyocardial fibroblast myocyte communication. Circ. Res.106(1), 47–57 (2010).
   PubMed Web of Science ®Google Scholar
• Bang C , BatkaiS, DangwalSet al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest.124(5), 2136–2146 (2014).
   PubMed Web of Science ®Google Scholar
• Hu B , Gharaee-KermaniM, WuZ, PhanSH. Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis. Am. J. Pathol.178(4), 1500–1508 (2011).
   PubMed Web of Science ®Google Scholar
• Wang J , LiewOW, RichardsAM, ChenYT. Overview of microRNAs in cardiac hypertrophy, fibrosis, and apoptosis. Int. J. Mol. Sci.17(5), pii:E749 (2016).
   Web of Science ®Google Scholar
• Van Rooij E , SutherlandLB, ThatcherJEet al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA105(35), 13027–13032 (2008).
   PubMed Web of Science ®Google Scholar
• Wang X , WangHX, LiYLet al. MicroRNA Let-7i negatively regulates cardiac inflammation and fibrosis. Hypertension66(4), 776–785 (2015).
   PubMed Web of Science ®Google Scholar
• Gray WD , FrenchKM, Ghosh-ChoudharySet al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ. Res.116(2), 255–263 (2015).
   PubMed Web of Science ®Google Scholar
• Barile L , LionettiV, CervioEet al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc. Res.103(4), 530–541 (2014).
   PubMed Web of Science ®Google Scholar
• Yang J , LiY, XueF, LiuW, ZhangS. Exosomes derived from cardiac telocytes exert positive effects on endothelial cells. Am. J. Transl. Res.9(12), 5375–5387 (2017).
   PubMed Web of Science ®Google Scholar
• Zhang Z , YangJ, YanW, LiY, ShenZ, AsaharaT. Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair. J. Am. Heart Assoc.5(1), pii:e002856 (2016).
   Web of Science ®Google Scholar
• Ibrahim AG , ChengK, MarbanE. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep.2(5), 606–619 (2014).
   PubMed Web of Science ®Google Scholar
• Zhu J , LuK, ZhangNet al. Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif. Cells Nanomed. Biotechnol. doi:10.1080/21691401.2017.13882491–12 (2017) ( Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Zhao Y , SunX, CaoWet al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int.2015, 761643 (2015).
   PubMed Web of Science ®Google Scholar
• Tseliou E , FouadJ, ReichHet al. Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles. J. Am. Coll. Cardiol.66(6), 599–611 (2015).
   PubMed Web of Science ®Google Scholar
• Tseliou E , ReichH, DeCouto Get al. Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and Tgf-β signaling. Basic Res. Cardiol.109(6), 443 (2014).
   PubMed Web of Science ®Google Scholar
• Gallet R , DawkinsJ, ValleJet al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J.38(3), 201–211 (2017).
   PubMed Web of Science ®Google Scholar
• Ke X , YangD, LiangJet al. Human endothelial progenitor cell-derived exosomes increase proliferation and angiogenesis in cardiac fibroblasts by promoting the mesenchymal-endothelial transition and reducing high mobility group box 1 protein B1 expression. DNA Cell Biol.36(11), 1018–1028 (2017).
   PubMed Web of Science ®Google Scholar
• Vandergriff AC , DeAndrade JB, TangJet al. Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int.2015, 960926 (2015).
   PubMed Web of Science ®Google Scholar
• Djudjaj S , BoorP. Cellular and molecular mechanisms of kidney fibrosis. Mol. Aspects Med.65, 16–36 (2019).
   PubMed Web of Science ®Google Scholar
• Benito-Martin A , UceroAC, ZubiriIet al. Osteoprotegerin in exosome-like vesicles from human cultured tubular cells and urine. PLoS ONE8(8), e72387 (2013).
   PubMed Web of Science ®Google Scholar
• Bruno S , GrangeC, CollinoFet al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS ONE7(3), e33115 (2012).
   PubMed Web of Science ®Google Scholar
• Glowacki F , SavaryG, GnemmiVet al. Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS ONE8(2), e58014 (2013).
   PubMed Web of Science ®Google Scholar
• Zhou H , YuenPS, PisitkunTet al. Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int.69(8), 1471–1476 (2006).
   PubMed Web of Science ®Google Scholar
• Mu J , PangQ, GuoYHet al. Functional implications of microRNA-215 in TGF-β1-induced phenotypic transition of mesangial cells by targeting CTNNBIP1. PLoS ONE8(3), e58622 (2013).
   PubMed Web of Science ®Google Scholar
• Min QH , ChenXM, ZouYQet al. Differential expression of urinary exosomal microRNAs in IgA nephropathy. J. Clin. Lab. Anal.32(2), (2018).
   Web of Science ®Google Scholar
• Koh W , ShengCT, TanBet al. Analysis of deep sequencing microRNA expression profile from human embryonic stem cells derived mesenchymal stem cells reveals possible role of let-7 microRNA family in downstream targeting of hepatic nuclear factor 4 alpha. BMC Genomics11(Suppl. 1), S6 (2010).
   PubMedGoogle Scholar
• He J , WangY, LuXet al. Micro-vesicles derived from bone marrow stem cells protect the kidney both in vivo and in vitro by microRNA-dependent repairing. Nephrology (Carlton)20(9), 591–600 (2015).
   PubMed Web of Science ®Google Scholar
• Nagaishi K , MizueY, ChikenjiTet al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci. Rep.6, 34842 (2016).
   PubMed Web of Science ®Google Scholar
• Wu XM , GaoYB, XuLPet al. Tongxinluo inhibits renal fibrosis in diabetic nephropathy: involvement of the suppression of intercellular transfer of TGF-[Formula: see text]1-containing exosomes from GECs to GMCs. Am. J. Chin. Med.45(5), 1075–1092 (2017).
   PubMed Web of Science ®Google Scholar
• Elpek GO . Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J. Gastroenterol.20(23), 7260–7276 (2014).
   PubMed Web of Science ®Google Scholar
• Meng F , WangK, AoyamaTet al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology143(3), 765–776.e763 (2012).
   PubMed Web of Science ®Google Scholar
• Tan Z , QianX, JiangRet al. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J. Immunol.191(4), 1835–1844 (2013).
   PubMed Web of Science ®Google Scholar
• Seo W , EunHS, KimSYet al. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. Hepatology64(2), 616–631 (2016).
   PubMed Web of Science ®Google Scholar
• Huang G , BrigstockDR. Regulation of hepatic stellate cells by connective tissue growth factor. Front. Biosci. (Landmark Ed.)17, 2495–2507 (2012).
   PubMed Web of Science ®Google Scholar
• Loebel DA , TsoiB, WongN, TamPP. A conserved noncoding intronic transcript at the mouse Dnm3 locus. Genomics85(6), 782–789 (2005).
   PubMed Web of Science ®Google Scholar
• Watanabe T , SatoT, AmanoTet al. Dnm3os, a non-coding RNA, is required for normal growth and skeletal development in mice. Dev. Dyn.237(12), 3738–3748 (2008).
   PubMed Web of Science ®Google Scholar
• Zheng J , WangW, YuF, DongP, ChenB, ZhouMT. MicroRNA-30a suppresses the activation of hepatic stellate cells by inhibiting epithelial-to-mesenchymal transition. Cell. Physiol. Biochem.46(1), 82–92 (2018).
   PubMedGoogle Scholar
• Zeng C , WangYL, XieCet al. Identification of a novel TGF-β-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis. Oncotarget6(14), 12224–12233 (2015).
   PubMedGoogle Scholar
• Povero D , PaneraN, EguchiAet al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol. Gastroenterol. Hepatol.1(6), 646–663.e644 (2015).
   PubMed Web of Science ®Google Scholar
• Chen L , ChenR, KemperS, BrigstockDR. Pathways of production and delivery of hepatocyte exosomes. J. Cell. Commun. Signal.12(1), 343–357 (2018).
   PubMed Web of Science ®Google Scholar
• Phinney DG , DiGiuseppe M, NjahJet al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun.6, 8472 (2015).
   PubMed Web of Science ®Google Scholar
• Seki A , SakaiY, KomuraTet al. Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model. Hepatology58(3), 1133–1142 (2013).
   PubMed Web of Science ®Google Scholar
• Forbes SJ , NewsomePN. New horizons for stem cell therapy in liver disease. J. Hepatol.56(2), 496–499 (2012).
   PubMed Web of Science ®Google Scholar
• Aquino JB , BolontradeMF, GarciaMG, PodhajcerOL, MazzoliniG. Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma. Gene Ther.17(6), 692–708 (2010).
   PubMed Web of Science ®Google Scholar
• Tsai PC , FuTW, ChenYMet al. The therapeutic potential of human umbilical mesenchymal stem cells from Wharton’s jelly in the treatment of rat liver fibrosis. Liver Transpl.15(5), 484–495 (2009).
   PubMed Web of Science ®Google Scholar
• Li T , YanY, WangBet al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev.22(6), 845–854 (2013).
   PubMed Web of Science ®Google Scholar
• Vader P , MolEA, PasterkampG, SchiffelersRM. Extracellular vesicles for drug delivery. Adv. Drug Deliv. Rev.106(Pt A), 148–156 (2016).
   PubMed Web of Science ®Google Scholar
• Nastase MV , Zeng-BrouwersJ, WygreckaM, SchaeferL. Targeting renal fibrosis: mechanisms and drug-delivery systems. Adv. Drug Deliv. Rev.129, 295–307 (2018).
   PubMed Web of Science ®Google Scholar
• Cai S , ChengX, PanX, LiJ. Emerging role of exosomes in liver physiology and pathology. Hepatol. Res.47(2), 194–203 (2017).
   PubMed Web of Science ®Google Scholar
• Tian T , ZhuYL, ZhouYYet al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem.289(32), 22258–22267 (2014).
   PubMed Web of Science ®Google Scholar
• Hwang DW , ChoiH, JangSCet al. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using (99m)Tc-HMPAO. Sci. Rep.5, 15636 (2015).
   PubMed Web of Science ®Google Scholar
• Morishita M , TakahashiY, NishikawaMet al. Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J. Pharm. Sci.104(2), 705–713 (2015).
   PubMed Web of Science ®Google Scholar
• Tidball JG . Mechanisms of muscle injury, repair, and regeneration. Compr. Physiol.1(4), 2029–2062 (2011).
   PubMed Web of Science ®Google Scholar
• Russell SB , RussellJD, TrupinKMet al. Epigenetically altered wound healing in keloid fibroblasts. J. Invest. Dermatol.130(10), 2489–2496 (2010).
   PubMed Web of Science ®Google Scholar
• Hu L , WangJ, ZhouXet al. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci. Rep.6, 32993 (2016).
   PubMed Web of Science ®Google Scholar
• Zhang W , BaiX, ZhaoBet al. Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway. Exp. Cell Res.370(2), 333–342 (2018).
   PubMed Web of Science ®Google Scholar
• Wang L , HuL, ZhouXet al. Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci. Rep.7(1), 13321 (2017).
   PubMed Web of Science ®Google Scholar
• Zhao B , ZhangY, HanSet al. Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation. J. Mol. Histol.48(2), 121–132 (2017).
   PubMed Web of Science ®Google Scholar
• Ludwig N , WhitesideTL. Challenges in exosome isolation and analysis in health and disease. Int. J. Mol. Sci.20(19), pii:E4684 (2019).
   Web of Science ®Google Scholar