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Nicholas F Larusso - One of the best experts on this subject based on the ideXlab platform.
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specific inhibition of aqp1 water channels in isolated rat Intrahepatic Bile Duct units by small interfering rnas
Journal of Biological Chemistry, 2003Co-Authors: Patrick L Splinter, Anatoliy I Masyuk, Nicholas F LarussoAbstract:Cholangiocytes express water channels (i.e. aquaporins (AQPs)), proteins that are increasingly recognized as important in water transport by biliary epithelia. However, direct functional studies demonstrating AQP-mediated water transport in cholangiocytes are limited, in part because of the lack of specific AQP inhibitors. To address this issue, we designed, synthesized, and utilized small interfering RNAs (siRNAs) selective for AQP1 and investigated their effectiveness in altering AQP1-mediated water transport in Intrahepatic Bile Duct units (IBDUs) isolated from rat liver. Twenty-four hours after transfection of IBDUs with siRNAs targeting two different regions of the AQP1 transcript, both AQP1 mRNA and protein expression were inhibited by 76.6-92.0 and 57.9-79.4%, respectively. siRNAs containing the same percent of base pairs as the AQP1-siRNAs but in random sequence (i.e. scrambled siRNAs) had no effect. Suppression of AQP1 expression in cholangiocytes resulted in a decrease in water transport by IBDUs in response to both an inward osmotic gradient (200 mosm) or a secretory agonist (forskolin), the osmotic water permeability coefficient (P(f)) decreasing up to 58.8% and net water secretion (J(v)) decreasing up to 87%. A strong correlation between AQP1 protein expression and water transport in IBDUs transfected with AQP1-siRNAs was consistent with the decrease in water transport by IBDUs resulting from AQP1 gene silencing by AQP1-siRNAs. This study is the first to demonstrate the feasibility of utilizing siRNAs to specifically reduce the expression of AQPs in epithelial cells and provides direct evidence of the contribution of AQP1 to water transport by biliary epithelia.
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channel mediated water movement across enclosed or perfused mouse Intrahepatic Bile Duct units
American Journal of Physiology-cell Physiology, 2002Co-Authors: Ai Yu Gong, Anatoly I Masyuk, Patrick L Splinter, Robert C Huebert, Pamela S Tietz, Nicholas F LarussoAbstract:We previously reported the development of reproducible techniques for isolating and perfusing intact Intrahepatic Bile Duct units (IBDUs) from rats. Given the advantages of transgenic and knockout ...
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development and characterization of polarized primary cultures of rat Intrahepatic Bile Duct epithelial cells
Laboratory Investigation, 1996Co-Authors: Benjamin T Vroman, Nicholas F LarussoAbstract:The study of Intrahepatic Bile Duct epithelial cells (i.e., cholangiocytes) has been limited by the lack of a polarized in vitro model that allows easy access to both apical and basolateral cell surfaces. Therefore, we developed a cell line of polarized normal rat cholangiocytes (NRCs) and established conditions that produced a confluent monolayer of cells grown on collagen-coated filters of tissue culture inserts. We passaged NRCs at high density to collagen-coated, tissue-culture inserts and measured transepithelial electrical resistance. We evaluated ultrastructural features by transmission and scanning electron microscopy. gamma-glutamyl-transpeptidase (gamma GT) was visualized in cultured cells by enzyme histochemistry, and cytokeratin (CK)-7, CK-19, vimentin, and desmin staining was done by immunohistochemistry. We studied the biologic responsiveness and functional polarity of NRCs by measuring their levels of cyclic AMP after addition of forskolin with or without somatostatin to either the apical or basolateral chambers. When seeded with approximately 1 x 10(5) cells/cm2, the NRCs formed a confluent monolayer in 72 hr. Transepithelial electrical resistance increased over time, achieving a maximum of 625 (+- 25) ohms.cm2 by 1 week after confluence. Transmission and electron microscopy scanning showed the apical cell surface to be tightly packed with microvilli with a heterogeneous display of cilia ranging from none to 20 to 30 cilia/cell. On transmission, apically positioned tight junctions and vesicles were apparent; nuclei were oriented basally and the basolateral surface was characterized by membrane interdigitations. NRCs stained positively for the cholangiocyte marker proteins, gamma-glutamyl-transpeptidase, CK-7, and CK-19, and negative for the mesenchymal markers, vimentin, and desmin. Exposure of the basolateral (but not the apical) cell surface to somatostatin caused a 60% inhibition of forskolin-induced increases in intracellular levels of cyclic AMP, suggesting the presence of somatostatin receptors exclusively on the basolateral plasma membrane domain. We have developed a unique model of primary cultures of normal rat cholangiocytes in which the apical and basolateral surfaces are easily accessible; the cells develop intermediate-strength tight junctions, retain their cholangiocyte phenotype, display morphologic and functional polarity, and are responsive to hormones. This model should be useful for the assessment of vectorial transport of solutes and other constituents of blood and Bile, as well as for studying growth regulation of cholangiocytes.
Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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IntraDuctal papillary neoplasm of the Bile Duct extending superficially from the Intrahepatic to extrahepatic Bile Duct
Journal of gastroenterology, 2006Co-Authors: Atsushi Nanashima, Yorihisa Sumida, Naoe Tamaru, Yasuni Nakanuma, Takafumi Abo, Kenji Tanaka, Terumitsu Sawai, Toru Yasutake, Takeshi Nagayasu, Tomayoshi HayashiAbstract:IntraDuctal papillary neoplasm of the Bile Duct (IPNB) or liver is a recently noted rare disease, and its pathogenesis remains unclear. Here we present a case of IPNB with an interesting morphology, which was treated by resection of the right hemiliver and extrahepatic Bile Duct. A 79-year-old woman was found to have a high alkaline phosphatase level and slight dilatation of the right Intrahepatic Bile Duct on imaging studies. The right Intrahepatic Bile Duct became dilated over a 2-year period; however, no solid mass could be detected, and tumor markers were not elevated. Hepatic resection was scheduled because a mucin-producing Bile Duct carcinoma of the liver was suspected. A right hemihepatectomy was conDucted, and the extrahepatic Bile Duct was also resected after malignant cells were found in the surgical stump of the right Bile Duct and in the Bile itself. Macroscopically, diffuse dilatation of the Intrahepatic Bile Duct was noted, but no solid component or mucin within the Duct was found. Histopathological findings revealed carcinoma in situ, IPNB, in the majority of Intrahepatic Bile Ducts, with no lymph node metastasis, and it extended continuously to the epithelium of the common Bile Duct. No tumor recurrence or biliary dilatation was observed at follow-up 2 years after surgery. It is important to consider malignancy in the presence of a dilated Bile Duct and in the absence of any cause of occlusion. Complete resection of IPNB results in a good prognosis and no recurrence.
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pathology and pathogenesis of Intrahepatic Bile Duct loss
Journal of Hepato-biliary-pancreatic Surgery, 2001Co-Authors: Yasuni Nakanuma, Koichi Tsuneyama, Kenichi HaradaAbstract:In recent years, the pathology and pathogenesis of Bile Duct loss have been extensively studied, and a num-ber of hepatobiliary diseases have been added to the list of Ductopenic diseases. In addition, the biology of biliary epithelial cells is now being studied with respect to Bile Duct loss, as well as biliary epithelial neoplasia. In this review, recent advances in pathogenetic and pathological studies of Intrahepatic Bile Duct loss are described, with an emphasis on immune-mediated cholangiopathies. The Bile Duct loss, an acquired and pathologic process that occurs in the biliary tree, is recognizable as an absence of Bile Duct in an individual portad tract, and also as such absence in the vicinity of parallel running hepatic arterial branches that constitute the portal triad. Immunostaining with biliary cytokeratin and other carbohydrate materials is useful for the identification of biliary elements in the inflamed portal tracts or fibrous septa. The underlying processes responsible for Bile Duct loss include immunological, ischemic, infectious, metabolic, and toxic processes. Bile Duct loss in primary biliary cirrhosis and primary sclerosing cholangitis is immune-mediated, that in interventional radiology using hepatic arterial branches is related to biliary ischemia, while that in hepatic allograft rejection is related to both immunological and ischemic insults. Bacterial and viral cholangitis with Bile Duct loss is an example of infectious cholangitis. The biliary tree maintains its homeostasis by renewal and dropout, and Bile Duct loss occurs mainly via biliary apoptosis. In some patients with Bile Duct loss, such as occurs in drug-induced injuries, the Bile Ducts regenerate and finally redistribute in the liver, while in other types of Bile Duct loss, the loss is progressive and is followed by vanishing Bile Duct syndrome, leading to biliary cirrhosis or liver transplantation. More analysis of the biology of biliary epithelial cells is mandatory for the evaluation of the pathobiology of Bile Duct loss, as well as for the effective restoration of biliary epithelial cells, in Ductopenic liver diseases.
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expression of matrix proteinases during human Intrahepatic Bile Duct development a possible role in biliary cell migration
American Journal of Pathology, 1995Co-Authors: T Terada, Y Okada, Yasuni NakanumaAbstract:Primitive biliary cells are known to migrate from the Ductal plate into the mesenchyme during human Intrahepatic Bile Duct development, and this migration process is essential for normal development of Intrahepatic Bile Ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human Intrahepatic Bile Duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the Ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the Ductal plate. TIMP-1 and TIMP-2 were expressed in the Ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human Intrahepatic Bile Duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human Intrahepatic Bile Ducts.
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profiles of expression of carbohydrate chain structures during human Intrahepatic Bile Duct development and maturation a lectin histochemical and immunohistochemical study
Hepatology, 1994Co-Authors: M Tadashi D Terada, Yasuni NakanumaAbstract:We investigated expression of carbohydrate chain structures during human Intrahepatic Bile Duct development and maturation. Results of staining for ABH antigens were negative in the Ductal plate and biliary cells migrating into the mesenchyma but were positive in newly formed Bile Ducts in the fetal liver and in maturing Bile Ducts in the postnatal liver. Staining for Lewisa, sialyl Lewisa and Lewisb antigens was negative in the Ductal plate but positive in migrating biliary cells, newly formed Ducts and maturing Ducts. Staining for sialyl Lewisx antigen was positive in the Ductal plate, migrating biliary cells and newly formed Ducts but negative in the postnatal liver. Lewisy antigen staining was negative in the Ductal plate and migrating biliary cells but positive in newly formed Ducts and maturing Ducts. Staining for T and Tn antigens was negative in the Ductal plate, migrating biliary cells and newly formed Ducts but positive in maturing Ducts. Staining for Lewisx, sialyl Th and carcinoembryonic antigen was negative in all tissues. Receptors of Ulex europaeus agglutinin I and soybean agglutinin were absent in the Ductal plate, migrating biliary cells and newly formed Ducts but present in maturing large Ducts. Staining for receptors of concanavalin A and Ricnus communis agglutinin I was negative in the Ductal plate but positive in migrating biliary cells, newly formed Ducts and maturing Ducts. Staining for the receptor of succinylated wheat germ agglutinin was always positive. These findings suggest that carbohydrate chain structures change during Intrahepatic Bile Duct development and maturation and that new carbohydrate chain structures gradually emerge as Intrahepatic Bile Ducts develop and mature. (Hepatology 1994;20:388–397.)
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expression of tenascin type iv collagen and laminin during human Intrahepatic Bile Duct development and in Intrahepatic cholangiocarcinoma
Histopathology, 1994Co-Authors: Tadashi Terada, Yasuni NakanumaAbstract:Expression of tenascin, type IV collagen and laminin during human Intrahepatic Bile Duct development and in cholangiocarcinoma was examined by immunohistochemistry. In the developing hilar Bile Ducts, tenascin was expressed in the mesenchyme around the epithelial cells migrating from the Ductal plate into the mesenchyme at 10-14 weeks of gestation. Tenascin was also expressed in the mesenchyme around newly formed hilar Bile Ducts at 15-20 weeks of gestation, but its expression disappeared after 21 weeks of gestation. Type IV collagen and laminin were expressed around the Ductal plate, around epithelial cells migrating from the Ductal plate into the mesenchyme, and around newly formed hilar Bile Ducts, and their expression was present throughout fetal life. By contrast, in the development of peripheral Bile Ducts, tenascin expression was not found. Type IV collagen and laminin were identified around the Ductal plate, migrating epithelial cells and peripheral Bile Ducts. In cholangiocarcinoma, tenascin and type IV collagen were expressed in the stroma, but laminin was not identified. These findings suggest that tenascin may play a role in hilar Bile Duct development and that type IV collagen and laminin may play a role in both hilar and peripheral Bile Duct development. Expression of tenascin and type IV collagen in the stroma of cholangiocarcinoma may be the result of malignant transformation of Intrahepatic biliary epithelium; tenascin in peritumoral stroma may stimulate carcinoma cell proliferation and growth in cholangiocarcinoma.
Stacey S Huppert - One of the best experts on this subject based on the ideXlab platform.
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Intrahepatic Bile Duct regeneration in mice does not require hnf6 or notch signaling through rbpj
American Journal of Pathology, 2014Co-Authors: Teagan J Walter, Charles Vanderpool, Ashley Cast, Stacey S HuppertAbstract:The potential for Intrahepatic Bile Duct (IHBD) regeneration in patients with Bile Duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of Bile Duct insufficiency with liver epithelial cell–specific deficiencies in Hnf6 and Rbpj , a mediator of canonical Notch signaling. Albumin-Cre Hnf6 flox/flox Rbpj flox/flox mice initially developed no peripheral Bile Ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6 flox/flox Rbpj flox/flox mice mounted a Ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the Ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive Ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
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3 dimensional resin casting and imaging of mouse portal vein or Intrahepatic Bile Duct system
Journal of Visualized Experiments, 2012Co-Authors: Teagan J Walter, Erin E Sparks, Stacey S HuppertAbstract:In organs, the correct architecture of vascular and Ductal structures is indispensable for proper physiological function, and the formation and maintenance of these structures is a highly regulated process. The analysis of these complex, 3-dimensional structures has greatly depended on either 2-dimensional examination in section or on dye injection studies. These techniques, however, are not able to provide a complete and quantifiable representation of the Ductal or vascular structures they are intended to elucidate. Alternatively, the nature of 3-dimensional plastic resin casts generates a permanent snapshot of the system and is a novel and widely useful technique for visualizing and quantifying 3-dimensional structures and networks. A crucial advantage of the resin casting system is the ability to determine the intact and connected, or communicating, structure of a blood vessel or Duct. The structure of vascular and Ductal networks are crucial for organ function, and this technique has the potential to aid study of vascular and Ductal networks in several ways. Resin casting may be used to analyze normal morphology and functional architecture of a luminal structure, identify developmental morphogenetic changes, and uncover morphological differences in tissue architecture between normal and disease states. Previous work has utilized resin casting to study, for example, architectural and functional defects within the mouse Intrahepatic Bile Duct system that were not reflected in 2-dimensional analysis of the structure(1,2), alterations in brain vasculature of a Alzheimer's disease mouse model(3), portal vein abnormalities in portal hypertensive and cirrhotic mice(4), developmental steps in rat lymphatic maturation between immature and adult lungs(5), immediate microvascular changes in the rat liver, pancreas, and kidney in response in to chemical injury(6). Here we present a method of generating a 3-dimensional resin cast of a mouse vascular or Ductal network, focusing specifically on the portal vein and Intrahepatic Bile Duct. These casts can be visualized by clearing or macerating the tissue and can then be analyzed. This technique can be applied to virtually any vascular or Ductal system and would be directly applicable to any study inquiring into the development, function, maintenance, or injury of a 3-dimensional Ductal or vascular structure.
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genetic interactions between hepatocyte nuclear factor 6 and notch signaling regulate mouse Intrahepatic Bile Duct development in vivo
Hepatology, 2012Co-Authors: Charles Vanderpool, Erin E Sparks, Kari A Huppert, Maureen Gannon, Anna L Means, Stacey S HuppertAbstract:Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and Bile Duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in Bile Duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant Intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to Ductular proliferation and a decrease in the density of communicating peripheral Bile Duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y–related HMG box transcription factor 9). Conclusion: HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the Intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to Intrahepatic Bile Duct development and their effect on cholestatic liver disease phenotypes. (HEPATOLOGY 2012;55:232–242)
Julie E. Buring - One of the best experts on this subject based on the ideXlab platform.
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smoking alcohol and biliary tract cancer risk a pooling project of 26 prospective studies
Journal of the National Cancer Institute, 2019Co-Authors: Emma E Mcgee, Demetrius Albanes, Julie E. Buring, Sarah S Jackson, Jessica L Petrick, Alison L Van Dyke, Hansolov Adami, Gabriella Andreotti, Laura Beanefreeman, Amy Berrington De GonzalezAbstract:BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 Intrahepatic Bile Duct, 1208 extrahepatic Bile Duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic Bile Duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend 40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with Intrahepatic Bile Duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of Intrahepatic Bile Duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
T Terada - One of the best experts on this subject based on the ideXlab platform.
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biliary epithelial expression of muc1 muc2 muc3 and muc5 6 apomucins during Intrahepatic Bile Duct development and maturation an immunohistochemical study
American Journal of Pathology, 1995Co-Authors: M Sasaki, T Terada, Y Nakanuma, Y S KimAbstract:Phenotypic alterations of biliary epithelial cells such as changes in intermediate filament composition and presence of carbohydrate residues, occur during the development of Intrahepatic Bile Ducts. In this study, we examined the expression of MUC1, MUC2, MUC3, and MUC5/6 apomucins (mucin core proteins) by immunohistochemical means in the human Intrahepatic Bile Duct during its development and maturation. In the fetal liver, new Bile Ducts in the portal tracts, either at the hilar level (corresponding to the large Bile Ducts) or peripheral level (corresponding to the small Bile Ducts), frequently expressed MUC1 apomucin at their luminal surface. Ductal plates also focally expressed MUC1 apomucin. By contrast, in the postnatal liver, the biliary epithelial cells of Intrahepatic large Bile Ducts constantly expressed MUC3 apomucin, whereas those of small Bile Ducts did not. MUC2 and MUC5/6 apomucins were absent in the Intrahepatic biliary elements of the fetal as well as postnatal livers. These data suggest that the biliary epithelial cells switch MUC1 apomucin expression before birth to that of MUC3 after birth. This characteristic transition may be similar to the changes in the hepatocellular expression of alpha-fetoprotein and albumin during the perinatal period.
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expression of matrix proteinases during human Intrahepatic Bile Duct development a possible role in biliary cell migration
American Journal of Pathology, 1995Co-Authors: T Terada, Y Okada, Yasuni NakanumaAbstract:Primitive biliary cells are known to migrate from the Ductal plate into the mesenchyme during human Intrahepatic Bile Duct development, and this migration process is essential for normal development of Intrahepatic Bile Ducts. However, its molecular mechanism is unknown. Matrix proteinases play an important role in cell migration during cancer invasion and organ development. In this study, we therefore investigated in situ expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) during human Intrahepatic Bile Duct development, using 32 human fetal livers. We also examined in situ expression of trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B, which are matrix proteinases and activators of MMP. MMP-1 expression was noted in the Ductal plate and migrating primitive biliary cells. MMP-2, MMP-3, and MMP-9 were expressed in the Ductal plate. TIMP-1 and TIMP-2 were expressed in the Ductal plate and migrating primitive biliary cells. Trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B were also expressed in primitive biliary cells. These data suggest that MMP, trypsinogen/trypsin, chymotrypsinogen/chymotrypsin, and cathepsin B play a critical role in biliary cell migration during human Intrahepatic Bile Duct development by degrading extracellular matrix proteins. The data also suggest that MMP inhibitors (TIMP-1 and TIMP-2) and MMP activators (trypsin, chymotrypsin, and cathepsin B) play an important role in biliary cell migration. The coordinated expression of MMP, MMP inhibitors, and MMP activators may be necessary for the normal development of human Intrahepatic Bile Ducts.
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detection of apoptosis and expression of apoptosis related proteins during human Intrahepatic Bile Duct development
American Journal of Pathology, 1995Co-Authors: T Terada, Y NakanumaAbstract:We investigated apoptosis by nick end labeling and the expression of apoptosis-related proteins by immunohistochemistry in fetal development of human Intrahepatic Bile Ducts and hepatocytes. During Intrahepatic Bile Duct development, apoptosis was present at all stages, and its positive ratio was high in the remodeling Ductal plate, moderate in the Ductal plate, and relatively low in remodeled Ducts. The cell proliferative activity as determined by proliferating cell nuclear antigen was also high in the remodeling Ductal plate, and relatively low in the Ductal plate and remodeled Ducts. fas antigen and c-myc protein were constantly positive in the Ductal plate, remodeling Ductal plate and remodeled Ducts. Bcl-2 protein was negative or faintly positive in the Ductal plate and remodeling Ductal plate, but was apparently positive in remodeled Ducts. Lewisy as detected by the BM-1 antibody was present in the Ductal plate, remodeling Ductal plate, and remodeled Ducts. p53 protein was not found in any cell types in the liver development. During hepatocyte development, many apoptotic and proliferating cell nuclear antigen-positive hepatocytes were noted. The developing hepatocytes expressed c-myc protein and fas antigen. Bcl-2 protein and Lewisy antigen were also weakly positive in the developing hepatocytes. These findings showed that balanced cell proliferation and apoptosis are involved in the normal development of Intrahepatic Bile Ducts and hepatocytes, and suggest that c-myc protein, fas antigen, Bcl-2 protein, and Lewisy antigen modulate apoptosis of fetal Intrahepatic biliary cells and hepatocytes, probably by stimulative (c-myc protein and fas and Lewisy antigens) or inhibitory (Bcl-2 protein) effects.