Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells.
It is well known that hepatic stellate cells (HSC) develop into cells, which are thought to contribute to liver fibrogenesis. Recent data suggest that HSC are progenitor cells with the capacity to differentiate into cells of endothelial and hepatocyte lineages. The present study shows that beta-catenin-dependent canonical Wnt signaling is active in freshly isolated HSC of rats. Mimicking of the canonical Wnt pathway in cultured HSC by TWS119, an inhibitor of the glycogen synthase kinase 3beta, led to reduced beta-catenin phosphorylation, induced nuclear translocation of beta-catenin, elevated glutamine synthetase production, impeded synthesis of alpha-smooth muscle actin and Wnt5a, but promoted the expression of glial fibrillary acidic protein, Wnt10b, and paired-like homeodomain transcription factor 2c. In addition, canonical Wnt signaling lowered DNA synthesis and hindered HSC from entering the cell cycle. The findings demonstrate that beta-catenin-dependent Wnt signaling maintains the quiescent state of HSC and, similar to stem and progenitor cells, influences their developmental fate.
Kordes
Claus
C
Clinic of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Sawitza
Iris
I
Häussinger
Dieter
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D051761:Paired Box Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D005974:Glutamate-Ammonia Ligase