Determining the effects of Wnt signaling in the alleviation of cholestasis via the promotion of hepatocyte transdifferentiation

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by bile duct inflammation and fibrosis, resulting in end‐stage liver disease and reduced life expectancy. Therefore, an effective treatment for PSC is needed. Hepatocytes exhibit remarkable plasticity and are known to be capable of transdifferentiating into cholangiocytes in models of biliary injury, which could create de novo ducts, repair damaged cholangiocytes, or contribute to bile detoxification. Previous studies utilizing in vitro organoid cultures and genetic mouse models found that β‐catenin and downstream targets are upregulated in hepatic organoid cultures, and mice expressing excess β‐catenin in the liver had an increased number of hepatocytes expressing cholangiocyte markers compared to wild type (WT) when subjected to cholestatic injury. These findings led to the hypothesis that Wnt/ß‐catenin signaling drives hepatocyte‐to‐cholangiocyte transdifferentiation during biliary injury. To test this hypothesis, we utilized lineage tracing in hepatic organoid cultures and TG mice expressing a mutated non‐degradable form of β‐catenin (S45D) in liver. We show that hepatocytes transdifferentiate to cholangiocytes in organoid cultures, and the cholangiocytes present are not from native contaminating cholangiocytes. We determined that TG mice fed DDC diet, which induces bile stasis, have: 1) improved serum ALP over time, indicating less biliary injury; 2) increased bile output compared to WT mice fed DDC diet; and 3) bile ducts populated with hepatocyte‐derived cholangiocytes. Through these studies we demonstrate that Wnt/ß‐catenin signaling catalyzes hepatocyte‐to‐cholangiocyte transdifferentiation, and activation of this pathway alleviates cholestasis in mouse models of PSC. Support or Funding Information NIH grant 1R01DK103775NIH training grant T32EB0010216NIH grant 1F31DK118802‐01