Skip to main content

Advertisement

SpringerLink
Log in

Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrosis. This study was designed to investigate the effect of exosomes derived from natural killer (NK) cells on HSC activation and liver fibrosis. The exosomes were isolated from NK-92MI cells (NK-Exo) and identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. Then NK-Exo was administered into TGF-β1-treated LX-2 cells (human HSC line) and mice with CCl4-induced liver fibrosis. LX-2 cell proliferation was determined by CCK-8 assay. The levels of α-SMA and CoL1A1 were measured by qRT-PCR and western blot to evaluate HSC activation. Serum levels of AST and ALT were measured. Hematoxylin–eosin, Masson staining, and Sirius Red staining were performed to assess the pathological changes and collagen deposition. Cell supernatant derived from NK-92MI cells inhibited TGF-β1-induced HSC proliferation and activation in LX-2 cells, and this effect was counteracted by the exosome inhibitor GW4869. Further assays confirmed that NK-Exo treatment significantly inhibited TGF-β1-induced HSC proliferation and activation. Moreover, NK-Exo administration alleviated CCl4-induced liver fibrosis in mice. NK-Exo inhibited TGF-β1-induced HSC activation and CCl4-induced liver fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37–55. https://doi.org/10.1016/j.mam.2018.09.002.

    Article  CAS  PubMed  Google Scholar 

  2. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27–422. https://doi.org/10.1016/j.addr.2017.05.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, et al. NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions. Blood. 2011;118(10):2784–92. https://doi.org/10.1182/blood-2011-04-347070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fasbender F, Widera A, Hengstler JG, Watzl C. Natural killer cells and liver fibrosis. Front Immunol. 2016;7:19. https://doi.org/10.3389/fimmu.2016.00019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gur C, Doron S, Kfir-Erenfeld S, Horwitz E, Abu-Tair L, Safadi R, et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut. 2012;61(6):885–93. https://doi.org/10.1136/gutjnl-2011-301400.

    Article  CAS  PubMed  Google Scholar 

  6. Glassner A, Eisenhardt M, Kramer B, Korner C, Coenen M, Sauerbruch T, et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Investig. 2012;92(7):967–77. https://doi.org/10.1038/labinvest.2012.54.

    Article  CAS  PubMed  Google Scholar 

  7. Zimmermann HW, Mueller JR, Seidler S, Luedde T, Trautwein C, Tacke F. Frequency and phenotype of human circulating and intrahepatic natural killer cell subsets is differentially regulated according to stage of chronic liver disease. Digestion. 2013;88(1):1–16. https://doi.org/10.1159/000350821.

    Article  PubMed  Google Scholar 

  8. Jeong WI, Park O, Suh YG, Byun JS, Park SY, Choi E, et al. Suppression of innate immunity (natural killer cell/interferon-gamma) in the advanced stages of liver fibrosis in mice. Hepatology (Baltimore, MD). 2011;53(4):1342–51. https://doi.org/10.1002/hep.24190.

    Article  CAS  Google Scholar 

  9. Jiao J, Ooka K, Fey H, Fiel MI, Rahmman AH, Kojima K, et al. Interleukin-15 receptor alpha on hepatic stellate cells regulates hepatic fibrogenesis in mice. J Hepatol. 2016;65(2):344–53. https://doi.org/10.1016/j.jhep.2016.04.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen L, Yao X, Yao H, Ji Q, Ding G, Liu X. Exosomal miR-103-3p from LPS-activated THP-1 macrophage contributes to the activation of hepatic stellate cells. FASEB J. 2020. https://doi.org/10.1096/fj.201902307RRR.

    Article  PubMed  Google Scholar 

  11. Shoae-Hassani A, Hamidieh AA, Behfar M, Mohseni R, Mortazavi-Tabatabaei SA, Asgharzadeh S. NK cell-derived exosomes from NK cells previously exposed to neuroblastoma cells augment the antitumor activity of cytokine-activated NK cells. J Immunother. 2017;40(7):265–76. https://doi.org/10.1097/cji.0000000000000179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Neviani P, Wise PM, Murtadha M, Liu CW, Wu CH, Jong AY, et al. Natural killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms. Cancer Res. 2019;79(6):1151–64. https://doi.org/10.1158/0008-5472.can-18-0779.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu L, Kalimuthu S, Gangadaran P, Oh JM, Lee HW, Baek SH, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics. 2017;7(10):2732–45. https://doi.org/10.7150/thno.18752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang JX, Xie P, Li YS, Wen T, Yang XC. Osteoclast-derived miR-23a-5p-containing exosomes inhibit osteogenic differentiation by regulating Runx2. Cell Signal. 2019. https://doi.org/10.1016/j.cellsig.2019.109504.

    Article  PubMed  Google Scholar 

  15. Huang W, Huang F, Lei Z, Luo H. LncRNA SNHG11 promotes proliferation, migration, apoptosis, and autophagy by regulating hsa-miR-184/AGO2 in HCC. Onco Targets Ther. 2020;13:413–21. https://doi.org/10.2147/OTT.S237161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kojima Y, Tsuchiya A, Ogawa M, Nojiri S, Takeuchi S, Watanabe T, et al. Mesenchymal stem cells cultured under hypoxic conditions had a greater therapeutic effect on mice with liver cirrhosis compared to those cultured under normal oxygen conditions. Regen Ther. 2019;11:269–81. https://doi.org/10.1016/j.reth.2019.08.005.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang M, Yang ZK, Liu H, Li RQ, Liu Y, Zhong WJ. Genipin inhibits the scleral expression of miR-29 and MMP2 and promotes COL1A1 expression in myopic eyes of guinea pigs. Graefe's Arch Clin Exp Ophthalmol. 2020. https://doi.org/10.1007/s00417-020-04634-7.

    Article  Google Scholar 

  18. Zheng J, Yu F, Dong P, Wu L, Zhang Y, Hu Y, et al. Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152. Oncotarget. 2016;7(39):62886–97. https://doi.org/10.18632/oncotarget.11709.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yang JJ, Yang Y, Zhang C, Li J, Yang Y. Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. J Cell Mol Med. 2020;24(4):2677–87. https://doi.org/10.1111/jcmm.14987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Prestigiacomo V, Weston A, Suter-Dick L. Rat multicellular 3D liver microtissues to explore TGF-beta1 induced effects. J Pharmacol Toxicol Methods. 2020;101:106650. https://doi.org/10.1016/j.vascn.2019.106650.

    Article  CAS  PubMed  Google Scholar 

  21. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology. 2006;130(2):435–52. https://doi.org/10.1053/j.gastro.2005.10.055.

    Article  CAS  PubMed  Google Scholar 

  22. Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol. 2007;1(1):173–80. https://doi.org/10.1586/17474124.1.1.173.

    Article  CAS  PubMed  Google Scholar 

  23. Shen M, Ren X. New insights into the biological impacts of immune cell-derived exosomes within the tumor environment. Cancer Lett. 2018;431:115–22. https://doi.org/10.1016/j.canlet.2018.05.040.

    Article  CAS  PubMed  Google Scholar 

  24. Fu J, Du H, Zhang X, Xu X. Pharmacological Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) channel alleviates carbon tetrachloride-induced liver fibrosis in mice. J Nippon Med Sch. 2019;86(5):258–62. https://doi.org/10.1272/jnms.JNMS.2019_86-407.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China

    Ling Wang & Jun Quan

  2. Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

    Yinghao Wang

Authors
  1. Ling Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinghao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Quan.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethical standards

All animal experiments were conducted under university guidelines and approved by the ethical committee for Animal Care and Use of the Xiangya Hospital of Central South University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, L., Wang, Y. & Quan, J. Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis. Human Cell 33, 582–589 (2020). https://doi.org/10.1007/s13577-020-00371-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-020-00371-5

Keywords

Search

Navigation