Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regeneration Defects in Livers of Mice With Mutations in Yap and Taz Caused by Bile Duct Disruption and Cholestasis

ABSTRACT: Background and aims: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs ranging from promoting proliferation to inhibiting it. Here, we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo’s role in growth control has been studied most intensely. Methods: We evaluated liver regeneration after CCl4 toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells and measured the behavior of different cell types during regeneration by histology, RNA-sequencing and flow cytometry. Results: We found that YAP/TAZ were activated in hepatocytes in response to CCl4 toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we show that Yap/Taz mutant bile ducts degenerated, causing cholestasis which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated PXR, which was sufficient to recapitulate the phenotype observed in mutant mice. Conclusions: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE157088 | GEO | 2020/11/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Hippo signaling instructs ectopic but not normal organ growth [Liver YapTazKO+CCl4]

Project description:We conditionally deleted Yap/Taz from hepatocytes prior to induction of acute injury by injection of liver toxin carbon tetrachloride (CCl4).

2022-11-19 | GSE211460 | GEO

Response of Hepatocytes to CCl4 Injury and Yap/Taz Knockout

Project description:Assessment of Hepatocytes in response to Yap/Taz knockout and also CCl4 injury

2019-09-01 | GSE113756 | GEO

Liver regeneration after cholestatic damage induced by Rbpj deletion

Project description:Liver cholestasis is a chronic liver disease (CLD) which belongs to a major health problem. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of ductular reactions. We investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of Rbpj, which represents a key regulator of Notch signalling, induces severe cholestasis through impaired IHBD maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with change of several signalling pathways including the Hippo pathway resulting in upregulation of SOX9, which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that Rbpj depletion is followed by deregulation of YAP/TEAD, which influences transdifferentiation of hepatocytes and thereby contributing to liver regeneration. In this study the liver regeneration process was analyzed in 4 weeks old Rbpj knockout mice and compared to 4 weeks old Rbpj wildtype mice.

2018-10-17 | GSE121302 | GEO

RNA-Sequencing analysis of liver tissue from female Foxa3-Cre YAP1 knockout mice, Foxa3-Cre YAP1 KO TAZ heterozygous mice, and WT littermate controls, at 3-4 months of age

Project description:We developed a mouse model of bile duct paucity by deleting Yes-associated protein 1 (YAP1) in foregut endoderm progenitors, using the Foxa3 promoter to drive Cre expression. YAP1 KO mice are viable postnatally and survive long-term despite a complete failure of intrahepatic bile duct development, resembling the liver phenotype of Alagille syndrome. Adult YAP1 KO mice suffer from severe chronic cholestasis, but show minimal hepatocellular injury, suggesting that the hepatocytes have adapted to preserve liver function and reduce damage from the toxicity of bile acids and bilirubin. We next bred Foxa3-Cre YAP1 KO TAZ heterozygote and Foxa3-Cre YAP1 KO TAZ KO (DKO) mice to assess the role of TAZ in this model. DKO mice and male YAP KO TAZ heterozygotes died around time of birth. The survivors, YAP1 KO TAZ heterozygote females, were overall phenotypically similar to YAP1 KO mice, with absence of intrahepatic bile ducts and long-term survival. We used RNA-seq to analyze the gene expression patterns of whole liver tissue of female adult YAP1 KO mice compared to WT controls (C57BL/6 background), and female adult YAP1 KO TAZ heterozygote (YKTH) mice compared to WT controls (mixed C57BL/6 - FVB background). We found that both YAP1 KO and YAP1 KO TAZ heterozygote female mice were overall very similar and showed similar alterations in gene expression compared to WT. There were a few differences in pathways involved in cell cycling and monocyte recruitment.

2023-07-20 | GSE213815 | GEO

Response of Hepatocytes to CCl4 Injury and Yap/Taz Knockout

Project description:Response of Hepatocytes to CCl4 Injury and Yap/Taz Knockout

| PRJNA453922 | ENA

Bile acid flux is necessary for normal liver regeneration

Project description:Bile acid return from the intestine and attendant signaling is necessary for liver regeneration after partial hepatectomy or CCl4 injury

2014-02-05 | GSE54673 | GEO

Bile acid flux is necessary for normal liver regeneration

Project description:Bile acid return from the intestine and attendant signaling is necessary for liver regeneration after partial hepatectomy or CCl4 injury Three groups of rat liver were examined at 4 time points (0, 4h, 12h, 24h) after partial hepatectomy; RNA from whole rat liver was isolated and deep sequencing was performed using the Illumina TruSeq platform

2014-02-05 | E-GEOD-54673 | biostudies-arrayexpress

A CRISPR loss-of-function Hepatic progenitor cells expansion screen in liver organoids

Project description:Biliary epithelial cells (BECs) form bile ducts in the liver, and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells which can form BEC-like organoids, suggesting RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles for this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found BECs lack and do not require LGR4/5-mediated WNT/β-Catenin signaling during DR, while YAP and mTORC1 signaling are required for this process. Upregulation of LGR5/AXIN2 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool and delineate signaling pathways involved.

2018-08-27 | GSE111269 | GEO

Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration

Project description:Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration The liver is an essential organ with compartmentalized metabolic processes and significant regenerative capabilities. Repopulation of the liver parenchyma can transpire from both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs). Here, we harness high-throughput single-cell RNA sequencing (scRNA-seq) to dissect the transcriptional heterogeneity and cellular diversity of these epithelial compartments in homeostasis and injury. Our data argue against the idea of a rigidly defined liver progenitor cell in BECs, finding instead that heterogeneity in homeostatic BECs is principally distinguished by a YAP-dependent program that defines a dynamic cellular state. We report that this cellular state dynamically fluctuates between BECs and can be induced in the majority of BECs in response to environmental stimuli and injury. Functional studies demonstrate that YAP is distinctly required for BEC survival in homeostasis, uncovering a tight physiological necessity for YAP signaling in BECs compared to other tissues. YAP is also essential for hepatocyte reprogramming towards a ductal progenitor fate upon injury. Finally, our data demonstrate that this YAP-driven cellular state is highly responsive to injury by physiological exposure to bile acids (BAs) via apical sodium-bile acid transporter, and that sequestration of endogenous BAs rescues the cell loss phenotype associated with homeostatic Yap deletion. Together, our findings uncover previously undescribed molecular heterogeneity within the ductal epithelium and highlight a distinct and potent role for YAP as a protective rheostat and regenerative regulator in the mammalian liver.

2019-05-08 | GSE125688 | GEO

A specific Peroxisome Proliferator-Activated Receptor (PPAR)-delta agonist is hepatoprotective and attenuates liver fibrogenesis

Project description:PPARδ is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle and liver. The aim of our study was to assess the effect of either the well-validated PPARδ agonist GW501516, or a novel PPARδ agonist KD3010 in mouse models of liver fibrosis. KD3010, but not GW501516, treated mice had markedly less liver injury induced by carbon tetrachloride (CCl4) injections. Deposition of extracellular matrix proteins was lower in the KD3010 group as compared to the vehicle or GW501516 treated group. Interestingly, profibrogenic CTGF was significantly induced by GW501516, but not KD3010, following CCl4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for three weeks. Hepatocytes were identified as targets for PPARδ agonist, and primary hepatocytes treated with KD3010 showed decreased serum starvation or CCl4-induced cell death, while GW501516 treated hepatocytes were not protected. KD3010 treatment of hepatocytes decreased reactive oxygen species (ROS) production after CCl4 exposure. In conclusion, our data demonstrate that a novel PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis. Given the oral availability and the favorable pharmacologic profile of KD3010, ligand activation of PPARδ represents an attractive and promising target for patients with chronic liver diseases. Total RNA was extracted from primary mouse hepatocytes treated with DMSO or PPARd agonists (KD3010, GW1516)

2012-04-18 | E-GEOD-32121 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data