Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage
Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage
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DOI：
10.1053/j.gastro.2008.04.038
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发表时间：
2008-08-01
期刊：
影响因子：
29.4
通讯作者：
Mertens, Peter R.
中科院分区：
文献类型：
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作者：
Dooley, Steven;Hamzavi, Jafar;Mertens, Peter R.
背景与目的：转化生长因子-β在肝脏中的促纤维化作用主要归因于肝星状细胞的激活和过量的基质合成。肝细胞被认为是导致细胞凋亡率增加的原因。方法：采用原代肝细胞突起和AML12细胞作为体外模型，检测转化生长因子-β对细胞表型和表达的影响。此外，转基因小鼠模型被用来确定肝细胞特异性Smad7表达在CCl4依赖损伤后肝纤维化中的结果。对慢性肝病患者的样本进行了肝细胞(部分)上皮向间充质转化(EMT)的评估。结果：在原代细胞培养和体内，大多数肝细胞存活，尽管激活了转化生长因子-β信号。这些细胞表现出表型变化，并表达(部分)EMT和纤维化的特有蛋白。与对照组相比，Smad7在小鼠肝细胞中的实验性表达减弱了转化生长因子-β信号转导和EMT，减少了间质胶原的积聚，并改善了CCl4诱导的肝损伤和纤维化评分。结论：肝细胞经历了依赖于转化生长因子-β的EMT样表型改变，并积极参与肝纤维化的形成。此外，在这种细胞类型中特异性地去除转化生长因子-β信号足以钝化纤维化反应。
Background & Aims: The profibrogenic role of transforming growth factor (TGF)-beta in liver has mostly been attributed to hepatic stellate cell activation and excess, matrix synthesis. Hepatocytes are believed to contribute to increased rates of apoptosis. Methods: Primary hepatocyte outgrowths and AML12 cells were used as an in vitro model to detect TGF-beta effects on the cellular phenotype and expression profile. Furthermore, a transgenic mouse model was used to determine the outcome of hepatocyte-specific Smad7 expression on fibrogenesis following CCl4-dependent damage. Samples from patients with chronic liver diseases were assessed for (partial) epithelial-to-mesenchymal transition (EMT) in hepatocytes. Results: In primary cell cultures and in vivo, the majority of hepatocytes survive despite activated TGF-beta signaling. These cells display phenotypic changes and express proteins characteristic for (partial) EMT and fibrogenesis. Experimental expression of Smad7 in hepatocytes of mice attenuated TGF-beta signaling and EMT, resulted in less accumulation of interstitial colla ens, and improved CCl4-provoked liver damage and fibrosis scores compared with controls. Conclusions: The data indicate that hepatocytes undergo TGF-beta-dependent EMT-like phenotypic changes and actively participate in fibrogenesis. Furthermore, ablation of TGF-beta signaling specifically in this cell type is sufficient to blunt the fibrogenic response.