Snail1 transcription factor is a critical mediator of hepatic stellate cell activation following hepatic injury

Abstract

Following liver injury, the wound-healing process is characterized by hepatic stellate cell (HSC) activation from the quiescent fat-storing phenotype to a highly proliferative myofibroblast-like phenotype. Snail1 is a transcription factor best known for its ability to trigger epithelial-mesenchymal transition, to influence mesoderm formation during embryonic development, and to favor cell survival. In this study, we evaluated the expression of Snail1 in experimental and human liver fibrosis and analyzed its role in the HSC transdifferentiation process. Liver samples from patients with liver fibrosis and from mice treated by either carbon tetrachloride (CCl(4)) or thioacetamide (TAA) were evaluated for mRNA expression of Snail1. The transcription factor expression was investigated by immunostaining and real-time quantitative RT-PCR (qRT-PCR) on in vitro and in vivo activated murine HSC. Snail1 knockdown studies on cultured HSC and on CCl(4)-treated mice were performed by adenoviral delivery of short-hairpin RNA; activation-related genes were quantitated by real-time qRT-PCR and Western blotting. Snail1 mRNA expression resulted upregulated in murine experimental models of liver injury and in human hepatic fibrosis. In vitro studies showed that Snail1 is expressed by HSC and that its transcription is augmented in in vitro and in vivo activated HSC compared with quiescent HSC. At the protein level, we could observe the nuclear translocation of Snail1 in activated HSC. Snail1 knockdown resulted in the downregulation of activation-related genes both in vitro and in vivo. Our data support a role for Snail1 transcription factor in the hepatic wound-healing response and its involvement in the HSC transdifferentiation process.

Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever

“…Thus, these findings favour the use of in vivo‐ activated HSC isolated from a fibrotic liver over in vitro‐ activated HSC , with in vivo‐ activated HSC reflecting more the specific microenvironment of HSC in the fibrotic liver. This model has been adapted by other investigators wishing to explore, in a more detailed manner, the interplay of HSC and their original microenvironment . Indeed, this concept has gained more attention and has been used to compare the behaviour of in vitro‐ activated with in vivo‐ activated HSC in different animal models/chronic diseases.…”

CD44v3-v10 reduces the profibrotic effects of TGF-β1 and attenuates tubular injury in the early stage of chronic obstructive nephropathy

“…TGF-␤1-induced upregulation of the profibrotic genes PAI-1, TGF-␤1, collagen type I, and ␣-SMA was more pronounced in CD44s overexpressing TEC and weaker/absent in CD44v3-TEC. Accordingly, CD44v3-TEC did not show an enhanced gene expression of the transcription factor Snail-1, which is known to trigger EMT (50). As changes in mRNAs may not always translate in similar protein expression levels, we determined PAI-1 protein levels by Western blot.…”

Hepatic Stellate Cell Culture Models

“…This model has now been adapted by several investigators to explore in greater detail the interplay between HSCs and the changing microenvironment in the diseased liver. Indeed, this concept has gained more attention and has been used to compare the characteristics of in vitro-activated HSCs with in vivo-activated HSCs in different animal models/chronic diseases [32][33][34]. Furthermore, fate tracking in combination with new markers in in vivo models has confirmed that activated HSCs are the major source of myofibroblasts and liver fibrosis [35,36].…”