Expression profile of fibroblast growth factors in hepatic stellate cells and experimental models of liver fibrosis

The fibroblast growth factor (FGF) family comprises 23 structurally related proteins divided in seven subfamilies. FGFs are major regulators of repair and wound healing in various tissues and organs. Also liver fibrosis can be considered as a wound healing process in response to chronic liver injury, and on a cellular level, the activation of hepatic stellate cells (HSC) is the key event of hepatic fibrosis. Although current therapies target FGF-receptors for the treatment of hepatocellular cancer, the expression and function of different FGFs in hepatic fibrosis is still very poorly understood.

The aim of this study was to perform a systematic profiling of FGF expression in HSC and experimental models of liver fibrosis.

Methods and Results:

Quantitative RT-PCR-analysis revealed that primary murine and human HSC express the following FGFs: (i) FGF1-subfamily: FGF-1/2, (ii) FGF4-subfamily: FGF-5, (iii) FGF7-subfamily: FGF-7/10/22, (iv) FGF8-subfamily: FGF-17/18, (v) FGF9-subfamily: FGF-9 and (vi) FGF19-subfamily: FGF-15/19/21/23. During the course of in vitro activation the following FGFs showed a significantly increased expression: (i) FGF-1/2, (iii) FGF-7/10, (iv) FGF-18, (v) FGF-9 and (vi) FGF-15/19/23. Increased FGF-expression was confirmed in different murine models of hepatic fibrosis (bile-duct-ligation, thioacetamide-induced toxic liver injury and diet-induced models of non-alcoholic steatohepatitis). Interestingly, analysis of activated HSC derived from 15 different human donors revealed significant variations in the FGF-expression pattern. Most pronounced differences showed FGF2, FGF5 and FGF7 expression levels which differed up to six-fold. FGF2 and FGF7 as well as FGF2 and FGF10 showed significant correlation. Comparison of FGF-expression patterns in different donors revealed that there are general “high” and “low” “FGF-expressors”.

Summary and conclusion:

We newly identified several FGFs as expressed by HSC and upregulated during HSC activation and during hepatic fibrosis, respectively. One may hypothesize that donor-to-donor variation in FGF-expression may also play a role in vivo affecting fibrosis development and progression. FGF10 and FGF18 have been shown to affect wounding and fibrosis in other organs and tissues such as the lung and the skin but have not been analyzed in the context of hepatic fibrosis until now. Further studies need to clarify the functional role of different FGFs in hepatic fibrosis and whether they can serve as therapeutic targets or prognostic factors.