Abstract
The expression of epidermal growth factor (EGF) is increased during liver fibrogenesis, and EGF receptor (EGFR) antagonist could attenuate liver fibrosis. Since EGFR is highly expressed by hepatocytes and cholangiocytes in cirrhotic liver, whether hepatic stellate cells express EGFR in response to EGF still needs exploration. Although EGFR antagonist could attenuate liver fibrosis, many ligands with EGF-like domains, besides EGF, can function through EGFR. Whether specifically blocking EGF could attenuate bile duct ligation (BDL)-induced liver fibrosis has not been revealed. BDL induced biliary infarcts and matrix deposition in mouse liver, and EGFR was expressed and phosphorylated by α-smooth muscle actin (αSMA)-positive myofibroblasts. LX-2 cells expressed EGFR, and these receptors were phosphorylated in the in vitro culture system. Growth curve and cell cycle analysis revealed that EGF could enhance cell proliferation of LX-2 cells. In addition, administration of EGF antibodies markedly reduced the EGF level in serum and the deposition of extracellular matrix in the liver of BDL mice when compared to IgG administration. Administration of EGF antibodies also reduced the phosphorylation of EGFR and the percentage of Ki-67-positive or PCNA-positive liver myofibroblasts of BDL mice when compared to IgG administration. Therefore, activated hepatic stellate cells express EGFR, thus being responsive to EGF signal, and administration of EGF antibodies could attenuate liver fibrosis by restricting the proliferation of myofibroblasts.
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Acknowledgements
We thank the Clinical Data and Biobank Resource of Beijing Friendship Hospital for storing liver samples. This work was supported by the grants from the National Natural Science Foundation of China (81570548 and 81100294), and the Chinese Foundation for Hepatitis Prevention and Control and the Wang Baoen Liver Fibrosis Foundation (Grant Number 2019073).
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PW contributed to the conception and design of the experiments. HX, LL, MC, TL, SS, HM, HY, and JJ contributed to the acquisition, analysis and interpretation of data. All authors participated in drafting and revising the manuscript and they all approved the final version of the manuscript for its submission.
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Xu, H., Liu, L., Cong, M. et al. EGF neutralization antibodies attenuate liver fibrosis by inhibiting myofibroblast proliferation in bile duct ligation mice. Histochem Cell Biol 154, 107–116 (2020). https://doi.org/10.1007/s00418-020-01867-9
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DOI: https://doi.org/10.1007/s00418-020-01867-9