Role of YAP in Liver Regeneration After Acetaminophen Overdose
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ABSTRACT:
PROVIDER: PRJNA759224 | ENA |
REPOSITORIES: ENA
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Project description:Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced acute liver failure (ALF) patients. We used affy microarrays to explore the mechanisms of transcriptional expression in YAP-KO mice after 300mg/kg APAP overdose.
2021-10-04 | GSE183119 | GEO
Project description:Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. Neuregulin-ErbB2 and Hippo-Yap signaling pathways are key mediators of CM proliferation and regeneration although the crosstalk between these pathways is unclear. Here, we demonstrate in mice that temporal over-expression (OE) of activated ErbB2 in CMs promotes cardiac regeneration in a heart failure model. Cellularly, OE CMs present an EMT-like regenerative response involving cytoskeletal reprograming, migration, ECM turnover, and displacement. Molecularly, we identified Yap as a critical mediator of ErbB2 signaling. In OE CMs, Yap interacts with nuclear envelope and cytoskeletal components, reflective of the altered mechanic state elicited by ErbB2. Hippo-independent activating phosphorylation on Yap at S352 and S274 were enriched in OE CMs, peaking during metaphase. Viral overexpression of Yap phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ErbB2-mediated Yap mechanosensory signaling involving EMT-like characteristics, resulting in heart regeneration.
2020-08-21 | PXD020731 | Pride
Project description: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.
2020-11-02 | GSE157088 | GEO
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
Project description:Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the USA. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild type (Nampt+/+)-, heterozygous knockout (Nampt+/-)-, and overexpression (NamptOE)-mice were treated with overdose of acetaminophen, followed by histological, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen -induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, while the effects in NamptOE mice were least severe relative to Nampt+/+ mice. These findings support that NAMPT protects against acetaminophen induced ALI.
2018-04-03 | GSE110787 | GEO
Project description:Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence underlies this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury model a transcriptional signature associated with the induction of paracrine senescence is observed within twenty four hours, and is followed by one of impaired proliferation. In genetic models of hepatocyte injury and senescence we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended upon macrophage derived TGFβ1 ligand. In acetaminophen poisoning inhibition of TGFβ receptor 1 (TGFβR1) improved survival. TGFβR1 inhibition reduced senescence and enhanced liver regeneration even when delivered after the current therapeutic window. This mechanism, in which injury induced senescence impairs regeneration, is an attractive therapeutic target for acute liver failure.
2019-03-20 | GSE111828 | GEO
Project description:To elucidate the role of PPARα activation in liver progenitor cell-mediated liver regeneration, we used Tg(fabp10a:pt-β-catenin) zebrafish transgenic line where liver progenitor cell-mediated liver regeneration is induced by oncogene overexpression
2023-07-01 | GSE226923 | GEO
Project description:In this study we aimed to address how YAP elicits profound biological changes in murine liver, such as proliferation, regeneration and dedifferentiation. We demonstrated that YAP is a master regulatori of liver functions, that reshapes the enhancer landscape to control transcription of genes involved in metabolism, proliferation and inflammation.
2022-07-25 | GSE199068 | GEO
Project description:To study the global changes of liver transcriptome after acetaminophen overdose. To study the global changes of transcriptome in the liver after acetaminophen overdose. Eight week old female C57BL/6 mice were fasted for 24 hours prior to a single intraperitoneal injection of 350mg/kg of acetaminophen in phosphate buffer saline (PBS) (treatment group) or PBS (control group). The mice were euthanized at different time points post exposure; plasma and tissue samples were collected for pathological examination and biochemical analyses.
2013-05-03 | E-GEOD-42181 | biostudies-arrayexpress
Project description:To study the global changes of liver transcriptome after acetaminophen overdose. To study the global changes of transcriptome in the liver after acetaminophen overdose. Eight week old female C57BL/6 mice were fasted for 24 hours prior to a single intraperitoneal injection of 350mg/kg of acetaminophen in phosphate buffer saline (PBS) (treatment group) or PBS (control group). The mice were euthanized at different time points post exposure; plasma and tissue samples were collected for pathological examination and biochemical analyses.
2013-05-03 | E-GEOD-42178 | biostudies-arrayexpress