title: 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.
authors.affiliation: University of Padova, School of Pharmacy, Dept. of Histology, Microbiology and Medical Biotechnologies, Via A. Gabelli 63, 35121 Padova, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Scarpa
authors.forename: Alessia R
authors.initials: AR
authors.lastname: Grillo
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.forename: Veronica
authors.initials: V
authors.lastname: Macchi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Stefani
authors.forename: Sara
authors.initials: S
authors.lastname: Signori
authors.forename: Andrea
authors.initials: A
authors.lastname: Buda
authors.forename: Paolo
authors.initials: P
authors.lastname: Fabris
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Giordani
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caro
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.forename: Diego
authors.initials: D
authors.lastname: Martines
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D002908:Chronic Disease; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007158:Immunologic Techniques; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000071250:Snail Family Transcription Factors; D013853:Thioacetamide; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D013853:Thioacetamide; D002251:Carbon Tetrachloride