Login Register Cart 0
Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

CD73 Blockade Alleviated Hepatic Fibrosis via Inhibiting Hepatic Stellate Cells Proliferation and Activation

Author(s): Lan Yang, Zhao-Wei Gao, Xia-Nan Wu, Chong Liu, Juan Zhang, Hui-Zhong Zhang and Ke Dong*

Volume 17, 2024

Published on: 13 July, 2023

Article ID: e220323214863 Pages: 11

DOI: 10.2174/1874467216666230322113039

open_access

conference banner
Abstract

Background: Liver fibrosis is associated with the activation of hepatic stellate cells (HSCs). Inhibition of HSCs activation is a strategy for alleviating hepatic fibrogenesis. CD73 is involved in liver disease development, while the mechanism remains unclear.

Objective: This study aimed to investigate the effect of CD73 targeting inhibition on liver fibrosis.

Methods: Intraperitoneal injection of CCl4 was used to induce liver fibrosis in mice models. Adenosine 5′-(α, β-methylene) diphosphate sodium salt (APCP) was used for CD73 blockade. The siRNA was used to induce CD73 knockdown in HSCs. LX2 and HSC-T6 were used to investigate the role of CD73 in HSCs activation in vitro.

Results: The results showed that APCP treatment could alleviate hepatic fibrosis. In fibrotic liver tissues, CD73 exhibited a positive correlation with markers of HSCs activation. Furthermore, APCP treatment and CD73 knockdown could inhibit HSCs (LX2 and HSC-T6) activation and proliferation. By using RNA sequencing of liver tissues from control, CCl4-mice, and APCP-treated mice, 851 genes that were significantly changed in CCl4 mice (vs. control) were reversed by APCP treatment. These genes were mainly enriched in cell division-associated biological processes. Moreover, we found that CD73 might be associated with autophagy in HSCs. In fibrotic liver tissues and HSCs, ATG5 and Beclin1 expression could be downregulated by CD73 knockdown and APCP treatment.

Conclusion: This study demonstrated the effects and mechanism of CD73 in HSCs activation and proliferation, which presents the therapeutical potential of CD73 blockage for liver fibrosis.

Keywords: CD73, Liver fibrosis, HSC activation, Autophagy, APCP treatment, Fibrotic liver tissues.

[1]
Caligiuri, A.; Gentilini, A.; Pastore, M.; Gitto, S.; Marra, F. Cellular and molecular mechanisms underlying liver fibrosis regression. Cells, 2021, 10(10), 2759.
[http://dx.doi.org/10.3390/cells10102759] [PMID: 34685739]
[2]
Kumar, S.; Duan, Q.; Wu, R.; Harris, E.N.; Su, Q. Pathophysiological communication between hepatocytes and non-parenchymal cells in liver injury from NAFLD to liver fibrosis. Adv. Drug Deliv. Rev., 2021, 176, 113869.
[http://dx.doi.org/10.1016/j.addr.2021.113869] [PMID: 34280515]
[3]
Li, J.; Deng, X.; Wang, S.; Jiang, Q.; Xu, K. Resolvin D1 attenuates CCl4 induced liver fibrosis by inhibiting autophagy-mediated HSC activation via AKT/mTOR pathway. Front. Pharmacol., 2021, 12, 792414.
[http://dx.doi.org/10.3389/fphar.2021.792414] [PMID: 34987404]
[4]
Mazza, G.; Al-Akkad, W.; Rombouts, K. Engineering in vitro models of hepatofibrogenesis. Adv. Drug Deliv. Rev., 2017, 121, 147-157.
[http://dx.doi.org/10.1016/j.addr.2017.05.018] [PMID: 28578016]
[5]
Luo, N.; Li, J.; Wei, Y.; Lu, J.; Dong, R. Hepatic stellate cell: A double-edged sword in the liver. Physiol. Res., 2021, 70(6), 821-829.
[http://dx.doi.org/10.33549/physiolres.934755] [PMID: 34717063]
[6]
Cai, X.; Wang, J.; Wang, J.; Zhou, Q.; Yang, B.; He, Q.; Weng, Q. Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacol. Res., 2020, 155, 104720.
[http://dx.doi.org/10.1016/j.phrs.2020.104720] [PMID: 32092405]
[7]
Foglia, B.; Novo, E.; Protopapa, F.; Maggiora, M.; Bocca, C.; Cannito, S.; Parola, M. Hypoxia, hypoxia-inducible factors and liver fibrosis. Cells, 2021, 10(7), 1764.
[http://dx.doi.org/10.3390/cells10071764] [PMID: 34359934]
[8]
Jia, W.; Zhou, T.; Dai, J.; Liu, Z.; Zhang, Y.; Zang, D.; Lv, X. CD73 regulates hepatic stellate cells activation and proliferation through Wnt/β-catenin signaling pathway. Eur. J. Pharmacol., 2021, 890, 173667.
[http://dx.doi.org/10.1016/j.ejphar.2020.173667] [PMID: 33121948]
[9]
Minor, M.; Alcedo, K.P.; Battaglia, R.A.; Snider, N.T. Cell type- and tissue-specific functions of ecto-5′-nucleotidase (CD73). Am. J. Physiol. Cell Physiol., 2019, 317(6), C1079-C1092.
[http://dx.doi.org/10.1152/ajpcell.00285.2019] [PMID: 31461341]
[10]
Alcedo, K.P.; Bowser, J.L.; Snider, N.T. The elegant complexity of mammalian ecto-5′-nucleotidase (CD73). Trends Cell Biol., 2021, 31(10), 829-842.
[http://dx.doi.org/10.1016/j.tcb.2021.05.008] [PMID: 34116887]
[11]
Nocentini, A.; Capasso, C.; Supuran, C.T. Small-molecule CD73 inhibitors for the immunotherapy of cancer: A patent and literature review. Expert Opin Ther Pat., 2017, 867-876.
[12]
Shuai, C.; Xia, G.; Yuan, F.; Wang, S.; Lv, X. CD39-mediated ATP-adenosine signalling promotes hepatic stellate cell activation and alcoholic liver disease. Eur. J. Pharmacol., 2021, 905, 174198.
[http://dx.doi.org/10.1016/j.ejphar.2021.174198] [PMID: 34033815]
[13]
Shen, M.; Li, Y.; Wang, Y.; Shao, J.; Zhang, F.; Yin, G.; Chen, A.; Zhang, Z.; Zheng, S. N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol., 2021, 47, 102151.
[http://dx.doi.org/10.1016/j.redox.2021.102151] [PMID: 34607160]
[14]
Luo, N.; Li, J.; Chen, Y.; Xu, Y.; Wei, Y.; Lu, J.; Dong, R. Hepatic stellate cell reprogramming via exosome-mediated CRISPR/dCas9-VP64 delivery. Drug Deliv., 2021, 28(1), 10-18.
[http://dx.doi.org/10.1080/10717544.2020.1850917] [PMID: 33336604]
[15]
Tan, Z.; Sun, H.; Xue, T.; Gan, C.; Liu, H.; Xie, Y.; Yao, Y.; Ye, T. Liver fibrosis: Therapeutic targets and advances in drug therapy. Front. Cell Dev. Biol., 2021, 9, 730176.
[http://dx.doi.org/10.3389/fcell.2021.730176] [PMID: 34621747]
[16]
Sun, P.; Zheng, X.; Li, X. The effects of CD73 on gastrointestinal cancer progression and treatment. J. Oncol., 2022, 2022, 1-8.
[http://dx.doi.org/10.1155/2022/4330329] [PMID: 35620732]
[17]
Yu, X.; Liu, W.; Wang, Z.; Wang, H.; Liu, J.; Huang, C.; Zhao, T.; Wang, X.; Gao, S.; Ma, Y.; Wu, L.; Li, X.; Yang, S.; Hao, J. CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: A promising target with non-canonical mechanisms. Cancer Lett., 2021, 519, 289-303.
[http://dx.doi.org/10.1016/j.canlet.2021.07.024] [PMID: 34302921]
[18]
Wirsdörfer, F.; de Leve, S.; Cappuccini, F.; Eldh, T.; Meyer, A.V.; Gau, E.; Thompson, L.F.; Chen, N.Y.; Karmouty-Quintana, H.; Fischer, U.; Kasper, M.; Klein, D.; Ritchey, J.W.; Blackburn, M.R.; Westendorf, A.M.; Stuschke, M.; Jendrossek, V. Extracellular adenosine production by ecto-5′-nucleotidase (CD73) enhances radiation-induced lung fibrosis. Cancer Res., 2016, 76(10), 3045-3056.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2310] [PMID: 26921334]
[19]
Perry, H.M.; Görldt, N.; Sung, S.J.; Huang, L.; Rudnicka, K.P.; Encarnacion, I.M.; Bajwa, A.; Tanaka, S.; Poudel, N.; Yao, J.; Rosin, D.L.; Schrader, J.; Okusa, M.D. Perivascular CD73 + cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment. Am. J. Physiol. Renal Physiol., 2019, 317(3), F658-F669.
[http://dx.doi.org/10.1152/ajprenal.00243.2019] [PMID: 31364375]
[20]
Fernández, P.; Perez-Aso, M.; Smith, G.; Wilder, T.; Trzaska, S.; Chiriboga, L.; Franks, A., Jr; Robson, S.C.; Cronstein, B.N.; Chan, E.S.L. Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis. Am. J. Pathol., 2013, 183(6), 1740-1746.
[http://dx.doi.org/10.1016/j.ajpath.2013.08.024] [PMID: 24266925]
[21]
de Leve, S.; Wirsdörfer, F.; Jendrossek, V. The CD73/Ado system—A new player in rt induced adverse late effects. Cancers, 2019, 11(10), 1578.
[http://dx.doi.org/10.3390/cancers11101578] [PMID: 31623231]
[22]
Peng, Z.; Fernandez, P.; Wilder, T.; Yee, H.; Chiriboga, L.; Chan, E.S.L.; Cronstein, B.N. Ecto-5′-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis. Nucleosides Nucleotides Nucleic Acids, 2008, 27(6-7), 821-824.
[http://dx.doi.org/10.1080/15257770802146403] [PMID: 18600546]
[23]
Liu, Z.; Wu, X.; Wang, Q.; Li, Z.; Liu, X.; Sheng, X.; Zhu, H.; Zhang, M.; Xu, J.; Feng, X.; Wu, B.; Lv, X. CD73-Adenosine A1R axis regulates the activation and apoptosis of hepatic stellate cells through the PLC-IP3-Ca2+/DAG-PKC signaling pathway. Front. Pharmacol., 2022, 13, 922885.
[http://dx.doi.org/10.3389/fphar.2022.922885] [PMID: 35784730]
[24]
Kitada, M.; Koya, D. Autophagy in metabolic disease and ageing. Nat. Rev. Endocrinol., 2021, 17(11), 647-661.
[http://dx.doi.org/10.1038/s41574-021-00551-9] [PMID: 34508250]
[25]
Wang, B.; Yang, H.; Fan, Y.; Yang, Y.; Cao, W.; Jia, Y.; Cao, Y.; Sun, K.; Pang, Z.; Du, H. 3-Methyladenine ameliorates liver fibrosis through autophagy regulated by the NF-κB signaling pathways on hepatic stellate cell. Oncotarget, 2017, 8(64), 107603-107611.
[http://dx.doi.org/10.18632/oncotarget.22539] [PMID: 29296191]
[26]
Zhao, J.; Peng, L.; Cui, R.; Guo, X.; Yan, M. Dimethyl α-ketoglutarate reduces CCl4-induced liver fibrosis through inhibition of autophagy in hepatic stellate cells. Biochem. Biophys. Res. Commun., 2016, 481(1-2), 90-96.
[http://dx.doi.org/10.1016/j.bbrc.2016.11.010] [PMID: 27823933]
[27]
Yang, R.; Hu, Z.; Zhang, P.; Wu, S.; Song, Z.; Shen, X.; Wei, Z. Probucol ameliorates hepatic stellate cell activation and autophagy is associated with farnesoid X receptor. J. Pharmacol. Sci., 2019, 139(2), 120-128.
[http://dx.doi.org/10.1016/j.jphs.2018.12.005] [PMID: 30638990]
[28]
Qiao, Z.; Li, X.; Kang, N.; Yang, Y.; Chen, C.; Wu, T.; Zhao, M.; Liu, Y.; Ji, X. A novel specific anti-CD73 antibody inhibits triple-negative breast cancer cell motility by regulating autophagy. Int. J. Mol. Sci., 2019, 20(5), 1057.
[http://dx.doi.org/10.3390/ijms20051057] [PMID: 30823477]
[29]
Shi, Q.; Wang, Q.; Chen, J.; Xia, F.; Qiu, C.; Li, M.; Zhao, M.; Zhang, Q.; Luo, P.; Lu, T.; Zhang, Y.; Xu, L.; He, X.; Zhong, T.; Lin, N.; Guo, Q. Transcriptome and lipid metabolomics-based discovery: Glycyrrhizic acid alleviates Tripterygium glycoside tablet-induced acute liver injury by regulating the activities of CYP and the metabolism of phosphoglycerides. Front. Pharmacol., 2022, 12, 822154.
[http://dx.doi.org/10.3389/fphar.2021.822154] [PMID: 35237151]
[30]
Jiang, Y.; Zhou, Y.; Song, S.; Fan, S.; Gao, Y.; Li, Y.; Huang, M.; Bi, H. St. john’s wort exacerbates acetaminophen-induced liver injury by activation of PXR and CYP-mediated bioactivation. Toxicol. Sci., 2022, 190(1), 54-63.
[http://dx.doi.org/10.1093/toxsci/kfac094] [PMID: 36073954]

Rights & Permissions Print Cite
Article Metrics
82
3
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy