TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1-Notch-Sox9 signaling...

Due to the inherent limitations of the mouse models, the molecular mechanism of TGFβ signaling involved in the development of intrahepatic bile ducts (IHBDs) has been investigated little. Here, we investigated the role of TGFβ signaling and its regulatory mechanism in IHBDs development. We demonstrate that TGFβ signaling pathway activity is essential for IHBDs development. When blocking TGFβ signaling at E10.5, the number of bile ducts in hilum was reduced more than two fold and number of CK19 positive chlangiocytes in periphery was reduced more than 3.5-fold compared with controls. We also show that alpha-smooth muscle actin (α-SMA)-immunoreactive cells are located in the portal vein mesenchyme (PVM) adjacent to the bile ducts during IHBDs development and identify the α-SMA positive cells expressing the Notch ligand Jagged1 in the periportal area. Importantly, after blocking TGFβ signaling, the expression of Jagged1 was selectively decreased in the PVM but not in biliary epithelial cells (BECs), which is associated with the transformation of portal mesenchyme cells (PMCs) into portal myofibroblasts (PMFs). In addition, Sox9, which is downstream of Notch, is decreased after blocking the TGFβ signaling pathway in the liver. Our findings uncover a novel mechanism of TGFβ signaling in controlling the development of IHBDs may through regulating the Jagged1-Notch-Sox9 signaling axis.