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PROVIDER: PRJNA1013270 | ENA |
REPOSITORIES: ENA
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Project description:Cholangiocyte organoids provide a powerful tool for characterizing bile duct epithelium and expanding cholangiocytes for tissue engineering purposes. However, this involves invasively obtained tissue-biopsies via surgery which is not preferential and limits the patient-specific capacities of these cultures. To overcome this, organoid culture were initiated from minimal invasive bile-samples obtained during routine clinical procedures. Characterization revealed that these bile-cholangiocyte organoids originate from the extrahepatic bile duct and are capable to repopulate human extrahepatic bile duct scaffolds. With this, bile duct tissue engineering as well as personalized disease modelling is in sight.
2020-11-19 | GSE156519 | GEO
Project description:Wollbold2014 - Effects of reactive oxygen
species
This model is described in the article:
Anti-inflammatory effects of
reactive oxygen species ¿ a multi-valued logical model
validated by formal concept analysis.
Wollbold J, Jaster R, Müller S,
Rateitschak K, Wolkenhauer O.
BMC Syst Biol 2014 Sep; 8(1): 101
Abstract:
BackgroundRecent findings suggest that in pancreatic acinar
cells stimulated with bile acid, a pro-apoptotic effect of
reactive oxygen species (ROS) dominates their effect on
necrosis and spreading of inflammation. The first effect
presumably occurs via cytochrome C release from the inner
mitochondrial membrane. A pro-necrotic effect ¿ similar to
the one of Ca2+ ¿ can be strong opening of mitochondrial
pores leading to breakdown of the membrane potential, ATP
depletion, sustained Ca2+ increase and premature activation of
digestive enzymes. To explain published data and to understand
ROS effects during the onset of acute pancreatitis, a model
using multi-valued logic is constructed. Formal concept
analysis (FCA) is used to validate the model against data as
well as to analyze and visualize rules that capture the
dynamics.ResultsSimulations for two different levels of bile
stimulation and for inhibition or addition of antioxidants
reproduce the qualitative behaviour shown in the experiments.
Based on reported differences of ROS production and of ROS
induced pore opening, the model predicts a more uniform
apoptosis/necrosis ratio for higher and lower bile stimulation
in liver cells than in pancreatic acinar cells. FCA confirms
that essential dynamical features of the data are captured by
the model. For instance, high necrosis always occurs together
with at least a medium level of apoptosis. At the same time,
FCA helps to reveal subtle differences between data and
simulations. The FCA visualization underlines the protective
role of ROS against necrosis.ConclusionsThe analysis of the
model demonstrates how ROS and decreased antioxidant levels
contribute to apoptosis. Studying the induction of necrosis via
a sustained Ca2+ increase, we implemented the commonly accepted
hypothesis of ATP depletion after strong bile stimulation.
Using an alternative model, we demonstrate that this process is
not necessary to generate the dynamics of the measured
variables. Opening of plasma membrane channels could also lead
to a prolonged increase of Ca2+ and to necrosis. Finally, the
analysis of the model suggests a direct experimental testing
for the model-based hypothesis of a self-enhancing cycle of
cytochrome C release and ROS production by interruption of the
mitochondrial electron transport chain.
This model is hosted on
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and identified by:
MODEL1407230001.
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2015-04-15 | MODEL1407230001 | BioModels
Project description:Microbial transformation of bile acids affects intestinal immune homeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. Additionally, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.
2024-02-09 | GSE253360 | GEO
Project description:The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined yet. In order to better characterize the role of c-Met in hepatocytes we generated a hepatocyte-specific c-Met knockout mouse (c-MetM-bM-^HM-^Fhepa) using the Cre-loxP system and studied its relevance after bile-duct ligation. Two strategies for c-Met deletion in hepatocytes were tested. Early deletion during embryonic development was lethal, while post-natal Cre-expression was successful leading to the generation of viable c-MetM-bM-^HM-^Fhepa mice. Bile-duct ligation in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-MetM-bM-^HM-^Fhepa mice revealed a significant reduction of anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-MetM-bM-^HM-^Fhepa mice showed a stronger apoptotic response after bile-duct ligation and Jo-2 stimulation. This phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-a and IL-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-b1, a-SMA, collagen-1a mRNA expression and enhanced collagen-fiber staining in c-MetM-bM-^HM-^Fhepa mice. For gene array analysis c-MetDhepa and c-MetloxP/loxP controls were stimulated for 2 hours with 2M-BM-5g recombinant mouse HGF.Three animals per group were treated in parallel, before and after i.p. injection of recombinant HGF or NaCl.
2009-02-18 | E-GEOD-13992 | biostudies-arrayexpress
Project description:DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome.
2024-05-02 | GSE231487 | GEO
Project description:The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined yet. In order to better characterize the role of c-Met in hepatocytes we generated a hepatocyte-specific c-Met knockout mouse (c-Met∆hepa) using the Cre-loxP system and studied its relevance after bile-duct ligation. Two strategies for c-Met deletion in hepatocytes were tested. Early deletion during embryonic development was lethal, while post-natal Cre-expression was successful leading to the generation of viable c-Met∆hepa mice. Bile-duct ligation in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met∆hepa mice revealed a significant reduction of anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-Met∆hepa mice showed a stronger apoptotic response after bile-duct ligation and Jo-2 stimulation. This phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-a and IL-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-b1, a-SMA, collagen-1a mRNA expression and enhanced collagen-fiber staining in c-Met∆hepa mice.
2009-02-18 | GSE13992 | GEO
Project description:Cholangiopathy is a diverse spectrum of chronic progressive bile duct disorders with limited treatment options and dismal outcome. Scaffold- and stem cell-based tissue engineering technologies hold great promise for the reconstructive surgery and tissue repair. Here, we report a combined application of 3D scaffold fabrication and direct reprogramming of the patient-specific human hepatocytes to a population of pluripotent stem cells to fabricate implantable artificial tissues that imitate mechanical and biological properties of the native bile ducts. The chemically derived hepatic progenitor cells (hCdHs) were generated using two small molecules A8301 and CHIR99021 and seeded inside the tubular scaffold engineered as synergistic combination of two layers. The inner electrospun fibrous layer was made of nanoscale-macroscale polycaprolactone fibers acting to promote the hCdHs attachment, alignment, and differentiation, while the outer microporous acellular foam layer served to increase mechanical stability. The two layers of fiber and foam were fused robustly together thus creating a coordinated mechanical flexibility to exclude any possible breaking or tear during surgery. The gene expression profiling and histochemical assessment confirmed that hCdHs acquired the biliary epithelial phenotype and filled the entire volume surface of fibrous matrix after two weeks of growth in cholangiocyte differentiation medium in vitro. The fabricated construct replaced the macroscopic part of the common bile duct (CBD) and re-stored the bile flow in a rabbit model of acute CBD injury. Animals which received the acellular scaffolds did not survive the replacement surgery. Thus, the artificial bile duct constructs populated with the patient-specific hepatic progenitor cells could provide a scalable and compatible platform for treating bile duct diseases.
2021-06-18 | GSE152809 | GEO
Project description:RNA-Sequencing was performed on mechanically dissociated, epithelial-enriched samples, of human extrahepatic biliary tissue from Gallbladder, Common Bile Duct, and Pancreatic Duct tissues. Sequencing was also performed on in vitro cultures of Organoid cell lines at passage 5 that were derived from human Gallbladder, Common Bile Duct, Pancreatic Duct, or Intrahepatic Bile Ducts.
2019-01-20 | E-MTAB-7569 | biostudies-arrayexpress
Project description:We investigated a drug-induced liver injury (DILI) model in rats induced by methapyrilene (MPy) administration. MPy, a former antihistamine and anticholinergic drug, was withdrawn in the 1970ties due to its ability to initiate hepatocarcinogenesis and is now used to induce hepatobiliary injury and biliary epithelial cell hyperplasia. Male Wistar rats (8–10 weeks old, weighing 170–200 g) were randomly assigned to three dosing groups (n=6 per group and time-point) and dosed with MPy at 0, 30 and 80 mg/kg/day by oral gavage. After 4, 8 or 15 days, or after 14 days followed by a recovery period of 10 days (day 24) rats were sacrificed. Increased levels of ALAT, ASAT, AP and ɣ-GT as well as bili-t and total bile acids indicated liver damage (AP and ɣGT indicating biliary effects). They were detectable on day 7 at the high dose of 80 mg/kg MPy and persisted until day 15 at end of treatment. Histopathologically, vacuolation and necrosis of the hepatocytes (predominantly in the periportal region) were seen starting on day 3 - especially in animals treated with 80 mg/kg MPy. These findings were accompanied by periportal mononuclear inflammatory cell filtration. Bile duct proliferation, bile duct hyperplasia and increased numbers of mitoses of hepatocytes were evident at all treatment time points. The frequency and severity of these findings increased with dose and duration of the treatment. Gene expression analysis in liver tissues revealed highly significant transcriptional changes in the high dose group, detectable on day 4 and intensifying over time. Besides genes associated with apoptosis (CASP4, CASP12), detoxification (CYB4B) and proliferation (p21, CCNG1) several were related to bile acid metabolism or transport. For example, bile acid exporters OATP1, NTCP, OATP4 and MOAT1/ OATPB as well as the putative bile acid metabolizing enzymes AMACR, BAAT and ACOX2 were found down regulated in response to MPy treatment. In contrast, mRNAs encoding putative bile acid importers MRP2 and ABCC4 / MRP4 were found up regulated. Most of the deregulated levels returned to control values during the recovery phase except OATP1, MOAT1/ OATPB, which remained slightly elevated. Interestingly, OATP4 followed an inverse trend of deregulation after 10 days of recovery, presumably due to overcompensation. Overall, the expression changes found associated with bile acid metabolism or transport could be linked to detected bile acid level alterations in liver and plasma.
2017-07-31 | GSE95470 | GEO
Project description:Genome wide DNA methylation profiling of normal and tumor bile duct samples. The Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles across approximately 450,000 CpGs in 138 tumor bile duct samples and 4 normal bile duct samples.
2017-07-03 | GSE89803 | GEO