Multimodal decoding of human liver regeneration [snrna_mouse]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223558 | GEO | 2023/02/01
REPOSITORIES: GEO
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Project description:Using snRNA-seq combined with spatial profiling of healthy and ALF explant human livers, we uncover a novel migratory hepatocyte subpopulation. We discover a corollary subpopulation in a mouse model of APAP-induced liver regeration, and demonstrate that this subpopulation meidates wound closure following liver injury.
2023-02-01 | GSE223560 | GEO
Project description:Using snRNA-seq combined with spatial profiling of healthy and ALF explant human livers, we uncover a novel migratory hepatocyte subpopulation. We discover a corollary subpopulation in a mouse model of APAP-induced liver regeration, and demonstrate that this subpopulation meidates wound closure following liver injury.
2023-02-01 | GSE223559 | GEO
Project description:Using snRNA-seq combined with spatial profiling of healthy and ALF explant human livers, we uncover a novel migratory hepatocyte subpopulation. We discover a corollary subpopulation in a mouse model of APAP-induced liver regeration, and demonstrate that this subpopulation meidates wound closure following liver injury.
2023-02-01 | GSE223581 | 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.
2024-04-15 | GSE255834 | 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.
2024-04-15 | GSE255777 | GEO
Project description:Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.
2022-08-12 | PXD029576 | Pride
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:In the recent study, we found that mesenchymal stem cell (MSC)-derived extracellular vesicles expressing the SIRPα protein (SIRP-EVs) were significantly distributed within myeloid cells (CD11b+ cells) and kupffer cells (CD11b+/F4/80+ cells) in acetaminophen (APAP)-induced mouse acute liver failure (ALF) model. Furthermore, SIRP-EVs enhanced the phagocytic activity of macrophages by blocking CD47 on necroptotic hepatocytes and promoted liver regeneration. Therefore, we investigated the therapeutic effects of SIRP-EVs on CD11b+ cells in APAP-induced ALF conditions. CD11b+ cells in the liver, including resident and recruited CD11b+ cells, were harvested and analyzed through bulk RNA sequencing.
2025-01-13 | GSE281951 | GEO
Project description:Acetaminophen (APAP) is one of the most widely consumed and prescribed drugs. APAP overdose is one of the leading causes of intrinsic drug-induced liver injury (DILI), acute liver failure (ALF), and liver transplantation in the Western world. Mg2+, essential for health, plays a role in virtually every process within the human cell. The cellular transporter family cyclin M, also known as CNNM, plays a key role in Mg2+ transport across the cell membranes in different organs. Here, we identified that the expression of CNNM4 is elevated in the liver of patients with APAP-induced liver injury (AILI), with a concomitant disturbance in serum Mg2+ levels. We demonstrated that, in the liver, APAP interferes with the Mg2+ mitochondrial reservoir via CNNM4, which affects ATP production and ROS generation, further boosting endoplasmic reticulum (ER) stress of the hepatocytes. Importantly, the CNNM4 mutant T495I showed no effect. Finally, a shift in localization of CNNM4 from membrane to ER was shown under APAP toxicity. Therapeutic targeting of Cnnm4 in the liver with nanoparticles and GalNAc-formulated siRNA provides efficient protection from AILI by restoring hepatocyte Mg2+ homeostasis and by inducing hepatocyte restoration. Our results suggest that inhibition of Cnnm4 may represent an alternative route for the treatment of DILI..
2023-03-11 | PXD036682 | Pride
