Prominin-1 promotes restitution of the murine extrahepatic biliary luminal epithelium following cholestatic liver injury
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ABSTRACT:
PROVIDER: PRJNA908254 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR22523158.fastq.gz | Fastqsanger.gz | |||
| SRR22523159.fastq.gz | Fastqsanger.gz | |||
| SRR22523160.fastq.gz | Fastqsanger.gz | |||
| SRR22523161.fastq.gz | Fastqsanger.gz | |||
| SRR22523162.fastq.gz | Fastqsanger.gz |
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Project description:Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury. Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands (PBGs) of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly more than ten-fold dilated PBGs following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility. We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.
2022-12-05 | GSE220054 | GEO
Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.
2020-06-30 | GSE144726 | GEO
Project description:Background and aimsRestitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury.Approach and resultsUtilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly >10-fold dilated peribiliary glands following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility.ConclusionsWe, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.
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Project description:These datasets look at the murine profile of extrahepatic biliary cells, primarily epithelial, in normal conditions and under mosaic Ctnnb1 gain of function.
2023-09-22 | GSE223099 | GEO
Project description:Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. We investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct and GB. We demonstrated that simultaneous activation of the Kras–Akt and Notch pathways in EHBD and GB resulted in the formation of BilINs and biliary cancer in a mouse model. Mechanistically, the Kras/Notch–Myc axis activates mTORC1 through phosphorylation of TSC2 in biliary tumorigenesis.
2023-05-04 | GSE231369 | GEO
Project description:Gene Expression of Single Extrahepatic Biliary Cells
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Project description:Newborn Balb/c mice were injected intraperitoneally with 1.5x10^6 fluorescent-forming units (ffu) of type- A Rhesus Rotavirus (RRV) or 0.9% normal saline (NS; control) within 24 hours of birth to induce experimental model of biliary atresia. Extrahepatic bile ducts including gallbladder were microdissected en bloc at 3, 7 and 14 days after RRV or saline injections. GeneChipM-BM-. Mouse Gene 1.0 ST Array (Affymetrix, CA) were used to screen mRNAs whose expression was differently regulated after RRV challenge compared to normal saline controls. Gene expression profiling: Each experimental conditon contains 3 sets of samples. Each sample consists of two to six extrahepatic bile ducts pooled prior to isolation of total RNA to ensure generation of adequate mRNA to perform quantitative experiments.
2013-06-01 | E-GEOD-46967 | biostudies-arrayexpress
Project description:Newborn Balb/c mice were injected with 1.5x10^6 fluorescent-forming units (ffu) of Rhesus rotavirus type-A or 0.9% NaCl (normal saline) intraperitoneally within 24 hours of birth to induce experimental model of biliary atresia. The extrahepatic bile ducts including gallbladder were microdissected en bloc at 3, 7 and 14 days after rhesus rotavirus or saline injection. GeneChipM-BM-. Mouse Gene 1.0 ST Array (Affymetrix, CA) were used to screen mRNAs whose expression was differently regulated after rhusus rotavirus injection compare to the normal saline controls. Gene expression profiling. Each experimental conditon has 3 sets of samples . Two to six extrahepatic bileducts were pooled prior to isolating total RNA depending on the size to ensure adequate RNA quantities to perform experiments quantifying mRNA expression.
2013-10-15 | E-GEOD-41594 | biostudies-arrayexpress
Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
2020-06-16 | GSE152494 | GEO
Project description:Despite the impact of bile duct disorders, treatment options remain very limited. Poor access to biliary tissue and restrictions in long-term culture or significant expansion of primary cholangiocytes have posed major challenges for research in the field. These limitations have so far precluded large scale experiments such as transcriptomic and genome-wide analyses which are urgently needed to better understand biliary physiology and pathophysiology. To address this issue, we have developed a novel system for the isolation and propagation of primary cholangiocytes from the extrahepatic bile ducts. The resulting Extrahepatic Cholangiocyte Organoids (ECOs) maintain their genetic stability, transcriptomic profile and function over long term culture and are compatible with regenerative medicine applications such as biliary reconstruction. We established a novel protocol for the isolation and propagation of primary cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs). The aim of this experiment was to provide in depth characterisation of the transcriptome of ECOs during long term culture. We compare the transcriptome of ECOs cultured for 1 passage (P1), 10 passages (P10) and 20 passages (P20) with freshly isolated primary cholangiocytes from the common bile duct. Embryonic Stem Cells (ES) cells are used as a negative control=
2017-07-04 | E-MTAB-4591 | biostudies-arrayexpress