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Elimination of Wnt secretion from stellate cells is dispensable for zonation and development of liver fibrosis following hepatobiliary injury

Rong Zhang, Alexander T Kikuchi, Toshimasa Nakao, Jacquelyn O Russell, Morgan E Preziosi, Minakshi Poddar, Sucha Singh, Aaron W Bell, Steven G England, Satdarshan P Monga
Gene Expression 2018 September 20
Background : Alterations in the Wnt signaling pathway including those impacting hepatic stellate cells (HSC) have been implicated in liver fibrosis. Methods : In the current study, we first examined the expression of Wnt genes in human HSC (HHSC) after treatment with a pro-fibrogenic factor TGFβ1. Next, we generated HSC-specific Wntless (Wls) knockout (KO) using the Lrat-cre and Wls-floxed mice. KO and littermate controls (CON) were characterized for any basal phenotype and subjected to two liver fibrosis protocols. Results : In vitro , TGFβ1 induced expression of Wnt2, 5a and 9a while decreasing Wnt2b, 3a, 4 and 11 in HHSC. In vivo , KO and CON mice were born at normal Mendelian ratio and lacked any overt phenotype. Loss of Wnt secretion from HSC had no effect on liver weight and did not impact β-catenin activation in the pericentral hepatocytes. After 7 days of bile duct ligation (BDL), KO and CON showed comparable levels of serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin. Comparable histology, Sirius red staining and immunohistochemistry for α-SMA, desmin, Ki67, F4/80 and CD45 indicated similar proliferation, inflammation and portal fibrosis in both groups. Biweekly administration of carbon tetrachloride for 4 or 8 weeks also led to comparable serum biochemistry, inflammation and fibrosis in KO and CON. Conclusion : Specific Wnt genes were altered in HHSC in response to TGFβ1; however, eliminating Wnt secretion from HSC did not impact basal β-catenin activation in normal liver, nor did it alter the injury-repair response during development of liver fibrosis.


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