Acute liver failure is regulated by MYC- and microbiome-dependent programs

Aleksandra A. Kolodziejczyk, Sara Federici, Niv Zmora, Gayatree Mohapatra, Mally Dori-Bachash, Shanni Hornstein, Avner Leshem, Debby Reuveni, Ehud Zigmond, Ana Tobar, Tomer Meir Salame, Alon Harmelin, Amir Shlomai, Hagit Shapiro, Ido Amit*, Eran Elinav*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1899-1911
Number of pages13
JournalNature Medicine
Volume26
Issue number12
DOIs
StatePublished - Dec 2020

Funding

FundersFunder number
Adelis Foundation
Daniel Morris Trust
Deutsch-Israelische Projektkooperation
Donald and Susan Schwarz
ERC-Cog724471-Hem-Tree2.0
Else Kroener Fresenius Foundation
European Crohn’s and Colitis Organization
European Union’s Horizon 2020 research and innovation program747114
Helen and Martin Kimmel
Helmholtz Foundation
Howard and Nancy Marks Charitable Fund
International Progressive MS Alliance/NMSSPA-1604-08459
Israel Ministry of Health
Israel Ministry of Science and Technology
Lawrence and Sandra Post Family Foundation
NeuroMac DFG
Park Avenue Charitable Fund
Pearl Welinsky Merlo Scientific Progress Research Fund
Thompson Family Foundation
Welcome Trust
Yael and Rami Ungar
Howard Hughes Medical Institute
Melanoma Research Alliance509044
Leona M. and Harry B. Helmsley Charitable Trust
European Research Council
Wolfson Foundation
EMBO2016‐1088
Garvan Institute of Medical Research
Israel Science Foundation703/15

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