Development of the biliary tract

The production of bile is an essential function of the liver. It contains cholesterol, bile acids, pigments and electrolytes, and their concentration is modified when the bile transits through the biliary tract. The bile is produced by the hepatocytes and is secreted into the bile canaliculi. These canaliculi are delineated by the apical membrane of the hepatocytes and are connected to the network of intrahepatic bile ducts (IHBD). The bile flows from the IHBD to the hepatic ducts, transits through the cystic duct and is stored in the gallbladder. It is excreted in the gut via the common bile duct. The hepatic, cystic and common bile ducts are collectively termed extrahepatic bile ducts and like the gallbladder and IHBD, their lumen is delineated by specialized cells called biliary epithelial cells (BEC) or cholangiocytes. Much attention has been paid in the past decade to the molecular control of liver development (reviewed in Darlington, 1999; Duncan, 2000, 2002; Zaret, 2000). However, the focus has mainly been on early liver development from the endoderm and on differentiation of hepatocytes. A number of recent papers now provide insight into the molecular mechanisms that regulate differentiation and morphogenesis of the biliary tract. Here we review these data and outline new questions on the molecular control of biliary development during embryogenesis. The morphogenesis of the IHBD is similar in humans, rats and mice (Van Eyken et al., 1988a,b; Desmet and Callea, 1990). A schematic description of this process is provided in Fig. 1 in which the timing corresponds to that in the mouse. Histologically, one can distinguish five steps in the development of the IHBD (Clotman et al., 2002). In the first step, occuring around embryonic day (E) 13.5–14.5, a subset of hepatoblasts strongly expresses biliary-specific cytokeratins. These cells are located at the site where ducts form, close to the portal mesenchyme, and are therefore considered as biliary precursor cells (Van Eyken et al., 1988b; Germain et al., 1988; Shiojiri, 1984a,b; 1994). At that stage, hepatoblasts expressing much lower levels of the same cytokeratins are also found throughout the parenchyma. In the second step, around E15.5, the biliary precursor cells form a continuous single-layered ring around the portal mesenchyme. This ring, now called ductal plate, becomes partly bilayered in the following step, which occurs around E16.5. In the fourth step, the ductal plate enters a phase of profound remodeling in which focal dilations appear between the two cell layers, giving rise to the bile ducts. The parts of the ductal plate not involved in the formation of the ducts progressively regress, and in the final stage, which starts around birth, the ducts are incorporated into the portal mesenchyme. Importantly, the formation of the IHBD occurs along a gradient from the hilum to the periphery of the liver. The timing of IHBD morphogenesis mentioned here corresponds to that of the most differentiated biliary structures found near the hilum. As to the extrahepatic bile ducts and the gallbladder, their development is less well characterized. In humans, the liver primordium which emerges from the endoderm consists of a cranial portion and a caudal portion (Shiojiri, 1997), and the extrahepatic bile ducts and the gallbladder arise from the latter portion. In mice, the boundary between these two portions is not well-defined.