Figure 3.

Process of the development of intrahepatic bile ducts (IHBDs). (A) A conventional model of bile duct morphogenesis. Cholangiocytes first form a cell layer, ductal plate, near the portal vein (PV) around E15 and then progressively reorganize it to tubules. (B) The transition from asymmetric to symmetric ducts. Cholangiocytes first generate the luminal space with hepatoblasts (“asymmetric duct” structure). Either by cholangiocytic differentiation of hepatoblasts in “asymmetric duct” or by reshaping the layer of cholangiocytes, the “symmetric duct structure” is generated. (C) The structures of IHBDs in 8W liver. The hierarchical luminal network containing large ducts and small mesh-like ductules covers the whole liver tissue in the adult (panel 2). 3D confocal imaging of the liver stained with anti-osteopontin (OPN) antibody also visualizes this hierarchical network (panel 3). Boxes in panels 1 and 2 are enlarged in panels 2 and 3, respectively. (D) The structures of IHBDs in E17 liver. The continuous homogeneous luminal network is established in E17 liver (panels 2 and 3). In the periphery, where the continuous luminal network has not been established, OPN⁺ cholangiocytes are discontinuously differentiated around the PV (panel 4). Boxes in panels 1 and 2 are enlarged in panels 2 and 3 ∼ 4, respectively. (E) The 3D model of IHBD morphogenesis. Cholangiocytes are discontinuously differentiated from hepatoblasts (panel 1), which are eventually interconnected to form the homogeneous luminal network in a Notch-signal-dependent manner (panel 2). The homogeneous luminal network is rearranged to the hierarchical one (panel 3). This transition is highly correlated with formation of the bile canalicular network.