肝再生
成纤维细胞生长因子受体
生物
成纤维细胞生长因子
基因敲除
癌症研究
成纤维细胞生长因子受体1
再生(生物学)
肝细胞
细胞生物学
内分泌学
内科学
受体
医学
细胞凋亡
生物化学
体外
作者
Susagna Padrissa-Altés,Marc Bachofner,Roman L. Bogorad,Lea Pohlmeier,Thomas Rossolini,Friederike Böhm,Gerhard Liebisch,Claus Hellerbrand,Victor Koteliansky,Tobias Speicher,Sabine Werner
出处
期刊:Gut
[BMJ]
日期:2014-11-21
卷期号:64 (9): 1444-1453
被引量:73
标识
DOI:10.1136/gutjnl-2014-307874
摘要
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 liver9s regenerative capacity.
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