CD73 regulates hepatic stellate cells activation and proliferation through Wnt/β-catenin signaling pathway
CD73 regulates hepatic stellate cells activation and proliferation through Wnt/β-catenin signaling pathway
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CD73通过Wnt/β-Catenin信号通路调节肝星状细胞的激活和增殖
DOI：
10.1016/j.ejphar.2020.173667
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发表时间：
2021-01-05
影响因子：
5
通讯作者：
Lv, Xiong-wen
中科院分区：
文献类型：
--
作者：
Jia, Wen-qian;Zhou, Tao-cheng;Lv, Xiong-wen
酒精性肝纤维化(ALF)通常与长期饮酒和肝星状细胞(HSCs)激活有关。抑制HSCs的激活和增殖是缓解肝纤维化的关键步骤。越来越多的证据表明，胞外-5‘-核苷酸酶(CD73)作为细胞外腺苷途径的重要组成部分，在肝脏疾病中发挥着重要作用。然而，CD73在ALF中的调节作用尚未阐明。本研究采用乙醇+CCl4诱导的小鼠肝纤维化模型和乙醛灭活的HSC-T6细胞模型，体内、外CD73的表达均持续升高。为建立ALF模型，从第5周至第8周，C57BL/6J小鼠腹腔注射CD73抑制剂腺苷5‘-(α，β-亚甲基)二磷酸钠(APCP)。结果表明，APCP可抑制HSCs的活化，减少纤维化标志物的表达，从而减轻ALF。沉默CD73可抑制HSC-T6细胞的活化，促进活化的HSC-T6细胞的凋亡。此外，HSC-T6细胞的增殖受到抑制，表现为细胞存活率下降和周期停滞。机制上，在乙醛激活的HSC-T6细胞中，Wnt/β-catenin通路被激活，CD73沉默或过表达可调节Wnt/β-catenin信号通路。总之，我们的研究揭示了CD73在HSCs激活中的作用，Wnt/β-catenin信号通路可能参与了这一过程。
Alcoholic liver fibrosis (ALF) is commonly associated with long-term alcohol consumption and the activation of hepatic stellate cells (HSCs). Inhibiting the activation and proliferation of HSCs is a critical step to alleviate liver fibrosis. Increasing evidence indicates that ecto-5'-nucleotidase (CD73) plays a vital role in liver disease as a critical component of extracellular adenosine pathway. However, the regulatory role of CD73 in ALF has not been elucidated. In this study, both ethanol plus CCl4-induced liver fibrosis mice model and acetaldehydeactivated HSC-T6 cell model were employed and the expression of CD73 was consistently elevated in vivo and in vitro. C57BL/6 J mice were intraperitoneally injected with CD73 inhibitor Adenosine 5'-(alpha, beta-methylene) diphosphate sodium salt (APCP) from 5th week to the 8th week in the development of ALF. The results showed APCP could inhibit the activation of HSCs, reduce fibrogenesis marker expression and thus alleviate ALF. Silencing of CD73 inhibited the activation of HSC-T6 cells and promoted apoptosis of activated HSC-T6 cells. What's more, the proliferation of HSC-T6 cells was inhibited, which was characterized by decreased cell viability and cycle arrest. Mechanistically, Wnt/beta-catenin pathway was activated in acetaldehyde-activated HSC-T6 cells and CD73 silencing or overexpression could regulate Wnt/beta-catenin signaling pathway. Collectively, our study unveils the role of CD73 in HSCs activation, and Wnt/beta-catenin signaling pathway might be involved in this progression.