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WIREs Dev Biol
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Molecular mechanisms of liver and bile duct development

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Abstract The liver is derived from the ventral foregut endoderm. After hepatic specification, liver progenitor cells delaminate from the endoderm and invade the septum transversum mesenchyme to form the liver bud. In addition to proliferation and expansion, liver progenitor cells differentiate into two epithelial cell types, each arranged into unique structures with distinctive function. Growth, morphogenesis, and differentiation during liver development are regulated by a variety of factors that are expressed in a spatially and temporally specific manner. A comprehensive understanding of the regulatory mechanisms underlying the liver development has influenced the diagnosis of liver diseases and further progress will be critical for future advances in therapy. This review highlights some of the best understood steps of liver development, summarizing progress in our understanding of the molecular mechanisms that underlie differentiation, morphogenesis, and functional integration of the liver. WIREs Dev Biol 2012 doi: 10.1002/wdev.47 For further resources related to this article, please visit the WIREs website.

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Adult liver architecture. (a) hematoxylin and eosin (H&E) staining of an adult mouse liver section, showing the portal vein, hepatic artery, bile duct, and central vein. The hepatocytes are divided into three different zones along the porto–central axis of the liver. The periportal region is called Zone 1, and the pericentral region is defined as Zone 3; the parenchymal part between Zones 1 and 3 is defined as Zone 2. Hepatocytes at different zones perform distinct metabolic functions. (b) Schematic representation of adult liver architecture. The apical sides of hepatocytes form the canaliculi while the basal sides face the endothelial sinusoids (only one bile canaliculus is shown in the cartoon, although every hepatocyte faces a bile canaliculus). Cholangiocytes (biliary epithelial cells, BECs) form the bile ducts close to the portal vein. The transition region connecting bile duct and canaliculus is called the Canal of Hering. The space between hepatocytes and sinusoids is called the space of Disse, and stellate cells reside within this space. Kupffer cells (liver macrophages) line the sinusoids together with endothelial cells. Bile produced by hepatocytes flows in a central‐to‐portal direction, from canaliculus to bile duct, while blood flows through the sinusoids in the opposite direction, from portal vein and hepatic artery to central vein. Periportal mesenchymal cells separate the portal triad (hepatic artery, portal vein, and bile duct) from the rest of the liver.

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Molecular regulation of extrahepatic bile duct (EHBD) differentiation. The EHBDs and the ventral pancreas are both derived from endoderm progenitors that express the transcription factors PDX1 and SOX17 at E8.5. At E10.5, these progenitor cells segregate into a PDX1+ pancreatic lineage and a SOX17+ extrahepatic biliary lineage. The SOX17 and hairy/enhancer of split‐1 (HES1) transcription factors determine the outcome of this cell fate decision; the extracellular signals that regulate this choice remain unknown. The extrahepatic ducts join with the intrahepatic ducts, which are separately derived from descendents of the hepatic domain. Transcription factors regulating intrahepatic bile duct development are shown in Figure 4.

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Intrahepatic bile duct (IHBD) morphogenesis. Hepatoblasts in contact with portal mesenchymal cells are induced to adopt a biliary fate. As a result of these signals, a structure called the ‘ductal plate’ surrounds the portal vein at approximate E15.5 of mouse development. Primitive bile ducts or tubules start to form at E16.5 with a unique feature of asymmetry: biliary type cells line the portal side of the lumen while hepatoblasts line the parenchymal side. The bile duct matures as the hepatoblasts lining the parenchymal side of the lumen complete a biliary differentiation program. The mature bile duct gradually becomes surrounded by portal mesenchyme.

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Zonation pattern of hepatocyte metabolic function. Although undistinguished by morphology, periportal, and pericentral hepatocytes express different genes and perform different metabolic functions. For instance, during the glucose metabolism, periportal hepatocytes mediate gluconeogenesis while pericentral hepatocytes mediate glycolysis, the opposing process. Zonation also governs the distribution of cells that mediate different aspects of ammonia metabolism and fatty acid metabolism.

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Control of hepatocyte/cholangiocyte lineage segregation. Hepatocytes and cholangiocytes are both derived from hepatoblasts, and several signals regulate this cell fate decision. Hepatoblasts in the periportal region give rise to cholangiocytes (biliary epithelial cells, BECs) and bile ducts as a result of signals localized in that region (blue). Hepatoblasts that do not receive these signals become hepatocytes. Hepatocytes and cholangiocyte identity is governed by a network of transcription factors, as shown (red).

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Formation of the liver bud. After hepatic specification around E8.5, hepatoblasts acquire a columnar shape, forming a liver diverticulum which is lined by a basement membrane and endothelial cells. At about E9.5 hepatoblasts undergo pseudostratification and interkinetic nuclear migration (INM), a homeobox protein (HHEX)‐ dependent process. After E9.5, the basement membrane begins to degrade and hepatoblasts migrate into the septum transversum mesenchyme (STM) to form the liver bud. PROX1 and TBX3 are necessary for hepatoblast migration at this stage. The onecut transcription factors ONECUT1 and ONECUT2 act redundantly to promote basement membrane degradation and hepatoblast migration.

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Specification of the hepatic domain within the ventral foregut endoderm. (a) The fate map of the prehepatic domain of ventral endoderm at around E8.25. Three spatially separated groups of endoderm cells, paired lateral domains, and the medial endoderm domain, converge to form the primitive liver. The paired lateral domains move toward the midline and fuse with the medial endoderm cells. Whereas the lateral endoderm cells give rise exclusively to the liver bud, the medial endoderm cells give rise to various midline tissues including the liver. (b) Liver specification at approximately E8.5. Fibroblast growth factor (FGF) signals from the cardiac mesoderm and BMP signals from the septum transversum mesenchyme (STM) induce the adjacent endoderm region to adopt a hepatic fate. WNT signaling also regulates liver specification.

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