Fibroblast growth factor receptor signalling is crucial for liver homeostasis and regeneration

Abstract

Several growth factors have been suggested to play a crucial role in liver regeneration, but a functional proof is still missing. Since fibroblast growth factors are important for the initiation of mammalian liver development, we determined the roles of these mitogens in liver repair by targeted expression of a dominant-negative fibroblast growth factor receptor (FGFR) in hepatocytes of transgenic mice. The liver of young animals appeared histologically normal, and liver function was not obviously impaired. In aged transgenic mice, the frequency of fatty liver development was strongly increased compared to control animals. Following partial hepatectomy, transgenic mice showed markedly reduced hepatocyte proliferation because of an arrest in the late G 1 phase of the cell cycle. These data demonstrate a key role of FGFR signalling in repair after liver injury.

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

“…The role of Wnt2b and Fgf signaling in the tomm22 MO regeneration model suggests a certain level of similarity between the pathways regulating liver development and regeneration. These findings are in agreement with a promoting role for Wnt2b and Fgf signaling in liver specification (Jung et al, 1999;Rossi et al, 2001;Ober et al, 2006;Shin et al, 2007), as well as in hepatocyte proliferation-based recovery post-PHx (Monga et al, 2001;Steiling et al, 2003;Sturm et al, 2004;Goessling et al, 2008;Kan et al, 2009). Although the Bmp pathway has also been shown to be involved in liver development (Rossi et al, 2001), as well as in regeneration postPHx (Steiling et al, 2003;Sturm et al, 2004;Sugimoto et al, 2007;Kan et al, 2009) or following tetrachloride-induced injury (Nakatsuka et al, 2007), we observed no clear role for Bmp signaling based on dorsomorphin treatments.…”

Reduced Expression of Fibroblast Growth Factor Receptor 2IIIb in Hepatocellular Carcinoma Induces a More Aggressive Growth

“…21 Further, we found that FGFR2-IIIb plays a critical role in liver regeneration and homeostasis. 22 Here, we show that FGFR2-IIIb expression is downregulated or lost in most HCC cell lines and tissues, and we provide evidence that reduced FGFR2-IIIb expression in HCC induces a more aggressive growth of HCC cells in vitro and in vivo.…”

“…12 Previously, we have shown that FGFR2-IIIb plays a critical role in liver regeneration and homeostasis. 22 Our data indicate that the growth limitation of FGFR2-IIIb re-expressing HCC cells is likely through maintenance of homeostasis or the balance among proliferation, apoptosis, and differentiation.…”

NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats

“…However, a contribution from other cell types in the liver such as hepatocytes cannot be excluded in the net anti-fibrotic effect of NP603. Some reports suggest that FGFR signaling pathways in hepatocytes are crucial regulators of liver regeneration (29). They also showed that blocking secretion of FGF-2 may inhibit survival pathways of hepatocytes and promote liver injury.…”