Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice
Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice
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DOI：
10.1136/gutjnl-2014-307874
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发表时间：
2015-09-01
期刊：
影响因子：
24.5
通讯作者：
Werner, Sabine
中科院分区：
文献类型：
--
作者：
Padrissa-Altes, Susagna;Bachofner, Marc;Werner, Sabine
目的成纤维细胞生长因子（Fibroblast growth factors, Fgfs）是细胞发育的关键调控因子，其在组织修复中的作用正在逐渐显现。在这里，我们研究了肝细胞上主要的Fgf受体（Fgfr） 4的诱导缺失（单独或与Fgfr1和Fgfr2联合）对ph后肝脏再生的影响。我们使用通过纳米颗粒传递的siRNA结合肝脏特异性基因敲除来研究Fgfr在肝脏再生中的功能。采用组织学、免疫组织化学、实时RT-PCR、western blotting和ELISA对肝脏或血液样本进行分析。结果sirna介导的Fgfr4敲低严重影响肝再生，导致肝细胞增殖受损并伴有肝坏死。在机制上，增殖缺陷是由Fgf15-Fgfr4-Stat3信号通路的抑制引起的，该信号通路是损伤诱导的Foxm1转录因子表达和随后的细胞周期进程所必需的，而肝内毒性胆汁酸水平升高被认为是坏死损伤的可能原因。Fgfr4敲低小鼠的肝脏肿块恢复失败至少部分是由肝细胞代偿性肥大阻止的。最重要的是，我们的数据揭示了肝脏中Fgf受体的部分冗余功能，因为在肝细胞中缺乏Fgfr1和Fgfr2的小鼠中，Fgfr4的敲低会导致PH后肝衰竭，导致严重的肝坏死和再生缺陷。这些结果表明，肝细胞中的Fgfr信号对于肝脏再生至关重要，并提示激活Fgfr信号是改善肝脏再生能力的一种有希望的方法。
Objective Fibroblast growth factors (Fgfs) are key orchestrators of development, and a role of Fgfs in tissue repair is emerging. Here we studied the consequences of inducible loss of Fgf receptor (Fgfr) 4, the major Fgf receptor (Fgfr) on hepatocytes, alone or in combination with Fgfr1 and Fgfr2, for liver regeneration after PH.Design We used siRNA delivered via nanoparticles combined with liver-specific gene knockout to study Fgfr function in liver regeneration. Liver or blood samples were analysed using histology, immunohistochemistry, real-time RT-PCR, western blotting and ELISA.Results siRNA-mediated knockdown of Fgfr4 severely affected liver regeneration due to impairment of hepatocyte proliferation combined with liver necrosis. Mechanistically, the proliferation defect resulted from inhibition of an Fgf15-Fgfr4-Stat3 signalling pathway, which is required for injury-induced expression of the Foxm1 transcription factor and subsequent cell cycle progression, while elevated levels of intrahepatic toxic bile acids were identified as the likely cause of the necrotic damage. Failure of liver mass restoration in Fgfr4 knockdown mice was prevented at least in part by compensatory hypertrophy of hepatocytes. Most importantly, our data revealed partially redundant functions of Fgf receptors in the liver, since knockdown of Fgfr4 in mice lacking Fgfr1 and Fgfr2 in hepatocytes caused liver failure after PH due to severe liver necrosis and a defect in regeneration.Conclusions These results demonstrate that Fgfr signalling in hepatocytes is essential for liver regeneration and suggest activation of Fgfr signalling as a promising approach for the improvement of the liver's regenerative capacity.