Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Aug:175:113816.
doi: 10.1016/j.addr.2021.05.026. Epub 2021 Jun 2.

Role of extracellular vesicles in liver diseases and their therapeutic potential

Enis Kostallari  1 , Shantha Valainathan  2 , Louise Biquard  3 , Vijay H Shah  4 , Pierre-Emmanuel Rautou  5
Affiliations
Review

Role of extracellular vesicles in liver diseases and their therapeutic potential

Enis Kostallari et al. Adv Drug Deliv Rev. 2021 Aug.

Abstract

More than eight hundred million people worldwide have chronic liver disease, with two million deaths per year. Recurring liver injury results in fibrogenesis, progressing towards cirrhosis, for which there doesn't exists any cure except liver transplantation. Better understanding of the mechanisms leading to cirrhosis and its complications is needed to develop effective therapies. Extracellular vesicles (EVs) are released by cells and are important for cell-to-cell communication. EVs have been reported to be involved in homeostasis maintenance, as well as in liver diseases. In this review, we present current knowledge on the role of EVs in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, primary liver cancers, acute liver injury and liver regeneration. Moreover, therapeutic strategies involving EVs as targets or as tools to treat liver diseases are summarized.

Keywords: Cirrhosis; Exosomes; Fibrosis; Microvesicles; Portal hypertension; Steatosis.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.. EVs in progression of nonalcoholic fatty liver disease (NAFLD).
Various lipotoxic stimuli enhance steatotic hepatocyte EV release. Released EVs carry biological cargo composed of proteins, DNA and lipids favoring infiltration of immune cells in the liver, underlying progression of liver inflammation. Other organs involved in NAFLD progression release EVs in the blood. They can either be taken up by the liver and contribute to development of liver inflammation and tissue remodeling or participate in systemic insulin resistance progression, which is a major driver of NAFLD progression. Prepared with Biorender.com.
Fig. 2.
Fig. 2.. EVs in progression of alcohol-associated liver disease (ALD).
Alcohol injury provokes an increased EV release by inhibition of autophagy pathway. Released EVs are enriched with various molecules (miRNAs, proteins, DNA) and exert effects on several liver cell types in the liver. They can activate hepatic stellate cells and contribute to fibrosis deposition. They are taken up by monocytes, macrophages and neutrophils, overall contributing to increased liver inflammation. Importantly, liver lipid accumulation can also be provoked by gut derived EVs. Prepared with Biorender.com.
Fig. 3.
Fig. 3.. EVs in cirrhosis and portal hypertension.
In the hepatic parenchyma, injured hepatocyte and endothelial cells release EVs able to activate quiescent HSCs and their migration, contributing to fibrosis deposition. Activated HSCs also emit EVs contributing to activation of quiescent HSCs in a vicious circle. Active HSC, injured hepatocytes and cholangiocytes release EVs inducing angiogenesis. Patients with cirrhosis have an increase of blood EVs containing TF, contributing to a pro-coagulant state. Cirrhosis induces an increase of liver resistance to blood flow, leading to portal hypertension (PH), associated with cirrhosis complications. Patients with cirrhosis have blood EVs that can be taken up by endothelial cells and act as phospholipid donors; they are metabolized into vasodilatary prostaglandins hindering normal smooth muscle cell contraction. This leads to an increase in blood flow in the hepatic artery, further causing progression of PH. Prepared with Biorender.com.
Fig. 4.
Fig. 4.. EVs in HBV and HCV infections.
HBV and HCV infection cause release of hepatocyte EVs that can be taken up by immune cells. In HBV infection, these EVs target NK cells and macrophages, promoting decrease of cell cytotoxicity and T cell activation by macrophages and therefore escape from host immune system. Hepatocyte also emit EVs supporting cancer cell proliferation. In HCV infection, hepatocyte-derived EVs are taken up by monocytes, which supports expansion of anti-inflammatory T-reg cells and apoptosis of HCV-specific T cells, all supporting escape from host immune system. These EVs can also be taken up by HSC and contribute to increased extracellular matrix deposition. Prepared with Biorender.com.
Fig. 5.
Fig. 5.. EVs in HCC.
Cancer cell-derived EVs can induce transformation of HSCs and macrophages into cancer-supporting cells. They promote tumor angiogenesis, cancer cell proliferation, epithelial-to-mesenchymal transition and secretion of pro-inflammatory cytokines, all contributing to tumor progression. Prepared with Biorender.com.
See this image and copyright information in PMC

References

    1. Marcellin P, Kutala BK, Liver diseases: a major, neglected global public health problem requiring urgent actions and large-scale screening, Liver Int. 38 (Suppl. 1) (2018) 2–6. - PubMed
    1. Paik JM, Golabi P, Younossi Y, Mishra A, Younossi ZM, Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD, Hepatology, 72 (2020) 1605–1616. - PubMed
    1. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F, Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease, Gastroenterology 149 (2015) 389–397 e310. - PMC - PubMed
    1. Bernal W, Auzinger G, Dhawan A, Wendon J, Acute liver failure, Lancet 376 (2010) 190–201. - PubMed
    1. Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl-Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-daSilva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D’Souza-Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekstrom K, El Andaloussi S, Elie-Caille C, Erdbrugger U, Falcon-Perez JM, Fatima F, Fish JE, Flores-Bellver M, Forsonits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez-Valero A, Gardiner C, Gartner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Gorgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ 2, Kornek M, Kosanovic MM, Kovacs AF, Kramer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lasser C, Laurent LC, Lavieu G, Lazaro-Ibanez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li IT, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Line A, Linnemannstons K, Llorente A, Lombard CA, Lorenowicz MJ, Lorincz AM, Lotvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SL, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG Jr., Meehan KL, Mertens I, Minciacchi VR, Moller A, Moller Jorgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-’t Hoen EN, Noren Hooten N, O’Driscoll L, O’Grady T, O’Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostergaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BC, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IK, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KM, Rughetti A, Russell AE, Saa P, Sahoo S, Salas-Huenuleo E, Sanchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schoyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PR, Silva AM, Skowronek A, Snyder OL 2, Soares RP, Sodar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BW, van der Grein SG, Van Deun J, van Herwijnen MJ, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ Jr., Veit TD, Vella LJ, Velot E, Verweij FJ, Vestad B, Vinas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MH, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yanez-Mo M, Yin H, Yuana Y, Zappulli V, Zarubova J, Zekas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK, Minimal information for studies of extracellular vesicles, (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines, J. Extracell Vesicles 7 (2018) (2018) 1535750. - PMC - PubMed

Publication types

MeSH terms