Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury

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Abstract

Hepatic injury and regeneration of the liver are associated with activation of hepatic stellate cells (HSC). Fibroblast growth factors (FGFs) and their receptors are important regulators of repair in various tissues. HSC express FGFR3IIIc as well as FGFGR4 and different spliced FGFR1IIIc and FGFR2IIIc isoforms which differ in the presence or absence of the acid box and of the first Ig-like domain. Expression of FGF9, known to be capable to activate the HSC FGFR2/3-isoforms, was increased in HSC in liver slice cultures after exposition to carbon tetrachloride, as an acute liver injury model. FGF9 significantly stimulated 3-H thymidine incorporation of hepatocytes, but failed to induce DNA synthesis in HSC despite the fact that FGF9 induced a sustained activation of extracellular signal-related kinases (ERK) 1/2. FGF9 induced an increased phosphorylation of Tyr436 of the fibroblast growth factor receptor substrate (FRS) 2, while phosphorylation of Tyr196 which is required for efficient Grb2 recruitment remained unchanged. Our findings suggest that HSC FGF9 provide a paracrine mitogenic signal to hepatocytes during acute liver injury, while the autocrine FGF9 signaling appears to be not sufficient to induce cell proliferation.

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Materials and methods

Preparation of cells and cell culture. Rat HSC were prepared from male Sprague–Dawley rats (about 500 g body weight) by the pronase/collagenase method as described before [6]. Hepatocytes were isolated following the collagenase method of Seglen as described [6]. Hepatocytes were seeded at a density of 5 × 104/cm2 on collagen coated dishes in Hepatozyme-SFM (Invitrogen, Heidelberg, Germany). Rat HSC, COS-1 cells, and the immortalized human hepatic stellate cell line LX-2 (a kind gift from Dr. S.L.

Expression of FGFR isoforms in HSC

Since FGF tyrosine kinase receptors bind FGFs with different binding affinities and alternative spliced variants exhibit unique FGF-binding specificity, we investigated the expression of the four FGF tyrosine kinase receptors in freshly isolated HSC and in HSC cultured for 3 days. To examine the expression of differentially spliced FGFR1, FGFR2, and FGFR3 isoforms by RT-PCR in detail, we first used oligonucleotide primers (set I depicted in Fig. 1A) that encompass the second half of Ig-like

Discussion

FGFs are thought to have a key role in tissue-repair processes and the involvement of HSC in liver regeneration and tissue repair is widely accepted. Here, we report for the first time that FGF9 is overexpressed in HSC during acute liver insult and we could show that FGF9 is highly mitogenic for primary hepatocytes suggesting that FGF9 secreted by HSC is acting in a paracrine mode on hepatocytes during liver repair. FGF9 is a secreted FGF and known to activate FGFR4, the main FGF receptor of

Acknowledgments

The authors are indebted to C. Kneip (Grünenthal GmbH, Aachen) and N. Sheron (University of Southampton) for their help and advice with the liver slice cultures. This work was supported by grants from the German Research Foundation to P.K. (KI 545/8-1) and C.H. (HE 2458/14-1).

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