Acute liver failure is regulated by MYC- and microbiome-dependent programs.
Acetaminophen
/ toxicity
Animals
Hepatic Stellate Cells
/ drug effects
Humans
Kupffer Cells
/ drug effects
Liver
/ drug effects
Liver Failure, Acute
/ chemically induced
Liver Transplantation
/ adverse effects
Mice
Microbiota
/ drug effects
Neutrophils
/ drug effects
Proto-Oncogene Proteins c-myc
/ genetics
Single-Cell Analysis
Thioacetamide
/ toxicity
Toll-Like Receptors
/ genetics
Transcriptome
/ drug effects
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
26
11
2019
accepted:
09
09
2020
pubmed:
28
10
2020
medline:
29
1
2021
entrez:
27
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33106666
doi: 10.1038/s41591-020-1102-2
pii: 10.1038/s41591-020-1102-2
doi:
Substances chimiques
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Toll-Like Receptors
0
Thioacetamide
075T165X8M
Acetaminophen
362O9ITL9D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1899-1911Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Commentaires et corrections
Type : CommentIn
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