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Id1 is a critical mediator in TGF‐β–induced transdifferentiation of rat hepatic stellate cells
Author(s) -
Wiercinska Eliza,
Wickert Lucia,
Denecke Bernd,
Said Harun M.,
Hamzavi Jafar,
Gressner A. M.,
Thorikay Midori,
ten Dijke Peter,
Mertens Peter R.,
Breitkopf Katja,
Dooley Steven
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21135
Subject(s) - transdifferentiation , hepatic stellate cell , mediator , microbiology and biotechnology , cancer research , medicine , chemistry , biology , stem cell
Transforming growth factor (TGF)‐β is critically involved in the activation of hepatic stellate cells (HSCs) that occurs during the process of liver damage, for example, by alcohol, hepatotoxic viruses, or aflatoxins. Overexpression of the TGF‐β antagonist Smad7 inhibits transdifferentiation and arrests HSCs in a quiescent stage. Additionally, bile duct ligation (BDL)‐induced fibrosis is ameliorated by introducing adenoviruses expressing Smad7 with down‐regulated collagen and α‐smooth muscle actin (α‐SMA) expression. The aim of this study was to further characterize the molecular details of TGF‐β pathways that control the transdifferentiation process. In an attempt to elucidate TGF‐β target genes responsible for fibrogenesis, an analysis of Smad7‐dependent mRNA expression profiles in HSCs was performed, resulting in the identification of the inhibitor of differentiation 1 (Id1) gene. Ectopic Smad7 expression in HSCs strongly reduced Id1 mRNA and protein expression. Conversely, Id1 overexpression in HSCs enhanced cell activation and circumvented Smad7‐dependent inhibition of transdifferentiation. Moreover, knock‐down of Id1 in HSCs interfered with α‐SMA fiber formation, indicating a pivotal role of Id1 for fibrogenesis. Treatment of HSCs with TGF‐β1 led to increased Id1 protein expression, which was not directly mediated by the ALK5/Smad2/3, but the ALK1/Smad1 pathway. In vivo , Id1 expression and Smad1 phosphorylation were co‐induced during fibrogenesis. In conclusion , Id1 is identified as TGF‐β/ALK1/Smad1 target gene in HSCs and represents a critical mediator of transdifferentiation that might be involved in hepatic fibrogenesis. (H EPATOLOGY 2006;43:1032–1041.)