Expression of paracrine fibroblast growth factors in hepatic stellate cells and hepatic fibrosis

Fibrosis is characterized by accumulation of extracellular matrix and is highly conserved following tissue injury. The regulation of fibroblast growth factor (FGF) signaling is a prerequisite for adequate wound healing in various organs. The FGF family contains 22 proteins that are divided in seven subfamilies and can be classified into paracrine, intracrine and endocrine factors. FGFs signal through tyrosine kinase FGF receptors (FGFRs). Hepatic fibrosis represents a chronic wound healing response and hepatocellular carcinoma (HCC) frequently develops in this “non-healing” wound. Although FGFRs are targets for the treatment of HCC, the expression of FGFs in hepatic fibrosis is still poorly understood.

The aim of this study was to analyze the expression of paracrine FGFs in HSC and hepatic fibrosis.

Methods and Results RT-qPCR revealed that primary murine and human HSC express following paracrine 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 and (v) FGF9-subfamily: FGF-9/16. During the course of in vitro HSC activation expression of following FGFs significantly increased: (i) FGF-1/2, (ii) FGF-5, (iii) FGF-7/10/22, (iv) FGF-18 and (v) FGF-9. Fitting to this, these FGFs were also elevated in murine models of hepatic fibrosis (bile-duct-ligation, thioacetamide-induced toxic liver injury and diet-induced models of non-alcoholic steatohepatitis). To enhance the dependability of our data, we analyzed the correlations between the FGFs and markers of hepatic stellate cell activation, COL1A1 and ACTA2 applying GEPIA database and GTEx dataset of human liver tissues. (i) FGF-1/2, (iii) FGF-7/10, (iv) FGF-18 and (v) FGF-9 significantly correlated with COL1A1 and ACTA2 indicating activated HSC as cellular source of FGFs. RT-qPCR analysis in activated HSC from human donors showed pronounced variations in FGF expression pattern indicating there are general high and low “FGF-expressors”.

Summary and conclusion Several paracrine FGFs are significantly upregulated during HSC activation and in experimental models of hepatic fibrosis. Also in human fibrotic liver tissues, HSC appear as major FGF-source. The observed donor-to-donor variation in FGF expression in activated HSC might play a role in the variability of the clinical course of liver fibrosis. Further studies are needed to elucidate the potential of defined FGFs as biomarkers or therapeutic targets in patients with chronic liver disease.

Publication History

Article published online:
04 January 2021