Yes‐associated protein promotes the proliferation and differentiation of liver progenitor cells during liver fibrosis
Yes‐associated protein promotes the proliferation and differentiation of liver progenitor cells during liver fibrosis
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DOI：
10.1096/fj.202201919r
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发表时间：
2023-04
期刊：
影响因子：
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通讯作者：
Zhenyang Shen;Weiming Dai;Yuecheng Guo;Junjun Wang;B. Shen;Binghang Li;Lungen Lu;X. Cai
中科院分区：
文献类型：
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作者：
Zhenyang Shen;Weiming Dai;Yuecheng Guo;Junjun Wang;B. Shen;Binghang Li;Lungen Lu;X. Cai
肝纤维化与肝祖细胞的增殖分化密切相关。是相关蛋白（雅普）是Hippo信号通路的关键效应分子，在调节细胞增殖和肝脏稳态中起重要作用。然而，其在肝纤维化过程中LPCs增殖和分化中的作用尚不清楚。通过免疫组织化学、免疫荧光染色、定量PCR和Western印迹，我们发现在胆碱缺乏、补充乙醇（CDE）饮食或3，5-二乙氧羰基-1，4-二氢可力丁（DDC）饮食诱导的纤维化小鼠以及肝纤维化患者中，LPCs扩增并增强LPCs中雅普的表达。通过注射Lgr 5启动子转录控制下的腺相关病毒载体，我们发现靶向敲除LPC中的雅普可减轻CDE/DDC饮食诱导的小管反应和肝纤维化。使用EdU掺入和Cell Counting Kit-8测定，我们证明了雅普可以调节LPC增殖。重要的是，脾移植过表达雅普的LPC提高了其分化为肝细胞的能力，并减轻了四氯化碳诱导的肝纤维化。总之，我们的研究结果表明，肝纤维化过程中LPCs的扩增和分化可以通过雅普调节，进一步表明操纵LPCs中雅普表达作为慢性肝病潜在治疗的可能性。
Liver fibrosis is closely related to the proliferation and differentiation of liver progenitor cells (LPCs). Yes‐associated protein (YAP) is a key effector molecule of the Hippo signaling pathway and plays an important role in regulating cell proliferation and liver homeostasis. However, its role in LPCs proliferation and differentiation during liver fibrosis are not well understood. Using immunohistochemistry, immunofluorescence staining, quantitative PCR and Western blotting, we discovered that LPCs expansion and enhanced YAP expression in LPCs in either choline‐deficient, ethionine‐supplemented (CDE) diet or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet‐induced fibrotic mice, as well as in patients with liver fibrosis. By injecting adeno‐associated virus vectors under the transcriptional control of Lgr5 promoter, we found that targeted knockdown of YAP in LPCs attenuated the CDE/DDC diet‐induced ductular reaction and liver fibrosis. Using EdU incorporation and Cell Counting Kit‐8 assays, we demonstrated that YAP can modulate LPCs proliferation. Importantly, spleen transplantation of YAP‐overexpressing LPCs improved their ability to differentiate into hepatocytes and alleviated carbon tetrachloride‐induced liver fibrosis. Collectively, our findings indicate that LPCs expansion and differentiation during liver fibrosis could be modulated by YAP, further suggesting the possibility of manipulating YAP expression in LPCs as a potential treatment for chronic liver diseases.