Development of extrahepatic bile duct excluding gall bladder in human fetuses: histological, histochemical, and immunohistochemical analysis.

BACKGROUND: The fetal development of extrahepatic bile ducts (EBD) is unkown. MATERIALS AND METHODS: Development of EBD was examined by immunohistochemistry in 16 fetuses of 7-40 gestational week (GW). Gall bladder (GB) was not investigated. RESULTS: At seven GW, a hepato-pancreatic bud (HPB) was seen near the hepatic hilus. At eight GW, embryonic EBD, GB and pacreas developed from HPB. Portal veins (PV) and hepatic arteries (HAs) were present in EBD at eight GW. Liver parenchyma was already present in seven GW. At eight GW, EBD at porta hepatis (PH) was already established; PH EBD was derived from ductal plate (DP). The distal and middle EBD gradually develeped and took shape of EBD at nine GW. In PH, cystic and hepatic ducts developed from DP at eight GW. EBD developed further, accompanying many nerve fibers (NF) at PH and distal and middle EBD. Apparent PV and HA were seen around 12 GW. Around 20 GW, HA and capillaries proliferated, giving rise to peribiliary capillary plexus (PCP) in all parts of EBD. EBD grew gradually further, and around 30 GW extrahepatic peribiliary glands (EPG) emerged from EBD but not from cystic duct. Around 36 GW, exocrine pancreatic acinar cells emerged from remodeled DP at PH. At term (40 GW), EBD was established but was as yet immature. Numerous NF were present around EBD. Histochemically, EBD epithelium had no mucins at 7-12 GW but contained neutral and acidic mucins at 23-40 GW. EPG had abundant neutral and acidic mucins. Immunohistochemically, alpha-fetoprotein (AFP) was consistently positive in the epithelial and mesenychyma. The NF and muscles of HPB present at seven GW were positive for neural cell adhesion molecule (NCAM), neuron-specific enolase (NSE), platelet-derived growth factor receptor-α (PDGFRA), and KIT, but they disappeared in nine GW. Expressions of cytokeratin (CK) seven and CK19 in EBD and EPG were slight or none, while expression of CK8 was moderate, and that of CK18 was strong. NF were positive for NCAM, NSE, synaptophysin, and chromogranin, and PDGFRA. MUC1 and MUC6 apomucins were noted in EBD and EPG. EPG contained numerous endocrine cells positive for chromogranin, synaptophysin, NCAM and NSE. A few endocrine cells positive for these antigens were seen in EBD. Numeous KIT-positive stem cells (SC) were seen in PH, EBD, PV, HA, PCP, and EPG. NCAM-positive and bcl-2-positive SC were also located in these structures. Epithelial cells of EBD and EPG showed expressions of MET, PDGFRA, CA19-9, MUC1, MUC2, MUC6, KIT, bcl-2, and ErbB2. No expressions of HepPar1, carcinoembryonic antigen (CEA), and epithelial membrane antigen (EMA) were noted. CONCLUSIONS: Although the findings have limitatios because this study of humans are descriptive one, the present data suggest that the processes of the development and differentiation of EBD system may be associated with EBD SC, CK prolifes, SFC/KIT signaling, HGF/MET signaling, PDGRa/PDGFRA signaling, fibroblast growth factor/ErbB2 signaling, neuroendocrine lineage, NF differentiation, pancreatic aninar cell differentiation, PCP differentiation, MUC apomucins differentiation, and expressions of AFP and CA19-9. HepPar1, EMA and CEA were not involved in them.

Defective development of the gall bladder and cystic duct in Lgr4- hypomorphic mice.

Leucine-rich repeat (LRR) -containing G protein coupled receptor (LGR) family members are characterized by the presence of a seven-transmembrane domain and LRR motifs. We describe a new function for Lgr4 in the development of the gall bladder and cystic duct and in the epithelium-mesenchyme interaction. Lgr4 expression was observed in the gall bladder epithelium when the gall bladder primordium elongated ventrally. Although Lgr4 hypomorphic mutant (Lgr4(Gt/Gt)) embryos developed a normal gall bladder bud at embryonic day (E) 10.25, no further elongation was observed at later stages. At E12.5, the mesenchyme surrounding the gall bladder had completely disappeared in Lgr4(Gt/Gt) embryos, while the gall bladder remained unelongated. Neighboring tissues such as liver and pancreas were unaffected, as revealed by expression of marker genes. This is the first report of a mutant mouse that lacks a gall bladder and cystic duct without affecting the other tissues that derive from the same hepatic diverticulum.

Development and differentiation of bile ducts in the mammalian liver.

The development and differentiation of bile ducts in the human and rodent liver are reviewed. The liver primordium develops as a ventral diverticulum in the anterior intestinal portal region, which consists of endodermal and mesodermal components. The endodermal cells differentiate into hepatocytes and all epithelial cells of the bile ducts in the adult liver. The gallbladder and extrahepatic bile ducts also start to develop from hepatic endodermal cells and hepatoblasts just after liver primordium formation. The gallbladder and cystic duct do not develop through hepatic development in the rat. Intrahepatic bile ducts are formed from periportal hepatoblasts forming the "ductal plate" and expressing alpha-fetoprotein, and albumin and bile duct-specific cytokeratin and develop independently of extrahepatic bile duct formation. The first sign of intrahepatic bile duct differentiation is the increased expression of bile duct-specific cytokeratin and large lumina formation in periportal hepatoblasts, and then deposition of basal laminar components occurs on the basal side. Their development takes place discontinuously along portal veins at the early stage of development, and they then become confluent through development. Periportal connective tissue, glucocorticoid hormones, and basal laminar components may play important roles in the differentiation of bile ducts.

[Development of the neural and tissue components of the excretory ducts of the liver, pancreas and Odd's sphincter in human embryogeny]. / Razvitie nervnykh i tkanevykh komponentov vyvodnykh protokov pecheni, podzheludochnoi zhelezy i sfinktera Oddi v émbriogeneze

The development of pancreatic, hepatic, cystic, common bile ducts, the Oddi's sphincter and their nervous apparatus were studied during prenatal human ontogenesis of fetuses and newborns. The process of formation of the nervous apparatus corresponds to the development of tissue structures of the ducts and the sphincter. The distinctions in the organization of nervous elements which are noted in adult humans are laid in the process of embryogenesis. These distinctions are especially pronounced in the structure of nervous plexuses and receptory endings. The nervous apparatus of the Oddi's sphincter region has a complex arrangement. This is the site of concentration of nerve nodules and receptory endings as well as abundant nervous connections between plexuses of the pancreatic head, duodenum and orifice zones of the both ducts. The receptors in nerve nodules and pericellular apparatuses on the bodies of ganglionic neurons were revealed.