RNAseq on Cxcr2hi hepatocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183161 | GEO | 2021/11/02
REPOSITORIES: GEO
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Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
2024-04-15 | GSE255777 | GEO
Project description:Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available singlenuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as Cxcl14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, Cxcl14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or Cxcl14 with a neutralizing antibody. We found that targeting Cxcl14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting the senescent hepatocyte had no effect. This data supports that the sustained induction of p21 in hepatocytes with persistent Cxcl14 secretion are critical mechanistic events leading to ALF in mice and human patients.
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Project description:Hepatic RNA specimens from mice (C57BL/6) of the 4 groups (vehicle-treated at 24h/48h, n=6; acetaminophen (APAP)-treated (300mg/kg) at 24h/48h, n=7) were pooled at equal shares. Thereafter, pooled RNA underwent analysis by 3'mRNA sequencing (MACE, GenXPro, Frankurt, Germany).
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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.
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Project description:Gene expression profiles of sandwich-cultured primary human hepatocytes exposed to 5 mM and 10 mM acetaminophen were used in a parallelogram approach in order to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Experiment Overall Design: Samples were retrieved from acetaminophen treated human hepatocyte cultures from 5 individuals (5 biological replicates). Experiment Overall Design: Human hepatocytes from each replicate were treated with 0, 5, and 10 mM acetaminophen for 24 h. Experiment Overall Design: This resulted in (3x5) 15 dual channel arrays on which control (0 mM acetaminophen) and reference samples (0, 5, and 10 mM acetaminophen) were hybridized.
2009-01-14 | E-GEOD-13430 | biostudies-arrayexpress
Project description:Gene expression profiles of sandwich-cutlured primary rat hepatocytes exposed to 5 mM and 10 mM acetaminophen were used in a parallelogram approach in order to compare gene expression responses between rat and human using in vitro cellular models, heaptocytes, and between rat in vitro and in vivo Experiment Overall Design: Samples were retrieved from acetaminophen treated rat hepatocyte cultures from 3 rats (3 biological replicates). Rat hepatocytes from each replicate were cultured in two culture conditions, each treated with 0, 5, and 10 mM acetaminophen for 24 h. This resulted in (3 rats x 2 culture conditions x 3 doses) 18 dual channel arrays on which control (0 mM acetaminophen) and reference samples (0, 5, and 10 mM acetaminophen) were hybridized
2009-01-14 | E-GEOD-13465 | biostudies-arrayexpress
Project description:Gene expression profiling of Pml wt and Pml KO mice liver with acetaminophen (apap) overdose (300mg/kg) i.p.
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Project description:3'mRNA sequencing of hepatic RNA (MACE) at the time points 24h/48h after acetaminophen (APAP) (300mg/kg) administration
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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.
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