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Acute liver failure is regulated by MYC- and microbiome-dependent programs
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Acute liver failure is regulated by MYC- and microbiome-dependent programs
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Journal Article
Acute liver failure is regulated by MYC- and microbiome-dependent programs
2020
Overview
Acute liver failure (ALF) is a fulminant complication of multiple etiologies, characterized by rapid hepatic destruction, multi-organ failure and mortality. ALF treatment is mainly limited to supportive care and liver transplantation. Here we utilize the acetaminophen (APAP) and thioacetamide (TAA) ALF models in characterizing 56,527 single-cell transcriptomes to define the mouse ALF cellular atlas. We demonstrate that unique, previously uncharacterized stellate cell, endothelial cell, Kupffer cell, monocyte and neutrophil subsets, and their intricate intercellular crosstalk, drive ALF. We unravel a common MYC-dependent transcriptional program orchestrating stellate, endothelial and Kupffer cell activation during ALF, which is regulated by the gut microbiome through Toll-like receptor (TLR) signaling. Pharmacological inhibition of MYC, upstream TLR signaling checkpoints or microbiome depletion suppress this cell-specific, MYC-dependent program, thereby attenuating ALF. In humans, we demonstrate upregulated hepatic MYC expression in ALF transplant recipients compared to healthy donors. Collectively we demonstrate that detailed cellular/genetic decoding may enable pathway-specific ALF therapeutic intervention.
A single-cell map of transcriptomic changes during acute liver failure unveils new insights into pathogenesis and potential therapeutic targets.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ Etiology
/ Failure
/ Genes
/ Hepatic Stellate Cells - drug effects
/ Hepatic Stellate Cells - metabolism
/ Humans
/ Kupffer Cells - drug effects
/ Liver
/ Liver Failure, Acute - chemically induced
/ Liver Failure, Acute - genetics
/ Liver Failure, Acute - pathology
/ Liver Transplantation - adverse effects
/ Mice
/ Microbiota (Symbiotic organisms)
/ Proto-Oncogene Proteins c-myc - genetics
/ Toll-Like Receptors - genetics
