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.
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Data availability
The small cytoplasmic RNA-seq data have been deposited with ArrayExpress under accession no. E-MTAB-8263, and 16S sequencing data with the European Nucleotide Archive under accession no. ERP116956. Source data are provided with this paper.
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Acknowledgements
We thank members of the Elinav laboratory and the DKFZ cancer-microbiome division for discussions. We thank C. Bar-Nathan for dedicated assistance with animal work. A.A.K. is a recipient of EMBO Long Term Fellowship no. 2016‐1088 and the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska‐Curie grant agreement no. 747114. I.A. is supported by the Chan Zuckerberg Initiative, an HHMI international scholar award, a European Research Council consolidator grant (ERC-COG, no. 724471-Hem-Tree2.0), the Thompson Family Foundation, an MRA established investigator award (no. 509044), the Israel Science Foundation (no. 703/15), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, a Helen and Martin Kimmel award for innovative investigation, a NeuroMac DFG/Transregional Collaborative Research Center grant, International Progressive MS Alliance/NMSS (no. PA-1604-08459), an Adelis Foundation grant and the SCA award of the Wolfson Foundation. E.E. is supported by Yael and Rami Ungar; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; the Pearl Welinsky Merlo Scientific Progress Research Fund; the Lawrence and Sandra Post Family Foundation; the Daniel Morris Trust; the Park Avenue Charitable Fund; the Hanna and Dr Ludwik Wallach Cancer Research Fund; the Howard and Nancy Marks Charitable Fund; Aliza Moussaieff; the estates of Malka Moskowitz, Myron H. Ackerman and Bernard Bishin (for the WIS-Clalit Program); Donald and Susan Schwarz; the V. R. Schwartz Research Fellow Chair; grants funded by the European Research Council; Israel Science Foundation; Israel Ministry of Science and Technology; Israel Ministry of Health; the Helmholtz Foundation; the Else Kroener Fresenius Foundation; the Garvan Institute; the European Crohn’s and Colitis Organization; Deutsch-Israelische Projektkooperation; and Welcome Trust. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair; a senior fellow, Canadian Institute of Advanced Research and an international scholar; and The Bill & Melinda Gates Foundation and Howard Hughes Medical Institute.
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A.A.K. and E.E. designed, analyzed and interpreted all experiments, and wrote the manuscript. A.A.K performed all experiments with the help of S.F., N.Z., G.M., S.H., A.L., M.D.-B. and H.S. D.R. and E.Z. provided experimental support. T.M.S. assisted with cell sorting. A.H. assessed tissue histology. A.T. and A.S. provided human clinical data, insights and material. I.A. and E.E. supervised the study.
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E.E. is a paid consultant at DayTwo and BiomX. None of this work is related to, funded or endorsed by, shared or discussed with or licensed to any commercial entity.
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Extended data
Extended Data Fig. 1 Acute liver failure model and characterisation of cell type.
a, Activity of hepatic enzymes aspartate transaminase (AST) and alanine transaminase (ALT) in serum of mice injected with APAP and TAA, significance was determined using one-sided Wilcoxon test; n = 5 for each group. Boxplot shows 25th to 75th percentiles with 50th denoted with a line, whiskers show 1.5 times interquartile range or maximum or minimum if they are smaller than that. b, FACS of retinoid fluorescence positive cells. c, Boxplot showing sum of normalised and scaled expression of MHCII in each cell type stellate quiescent n = 7282, stellate fibrotic n = 140, stellate activated (AAs) n = 6470, stellate cycling n = 180, stellate activated MYCi n = 2013, endothelial sinusoidal n = 5736, endothelial arterial n = 932, endothelial venous n = 167, endothelial activated (AAe) n = 4928, endothelial cycling n = 54, endothelial activated MYCi n = 2287, mesothelial n = 128, Kupffer n = 2696, Kupffer activated (AAk) n = 697, Kupffer activated MYCi n = 384, Kupffer MyD88 Trif KO n = 265, Kupffer activated MyD88 Trif KO n = 406, Kupffer cycling n = 155, macrophage Cx3cr1+ n = 280, monocyte Ly6C+ n = 5002, monocyte IFN n = 93, monocyte Ly6C- n = 293, plasmacytoid dendritic cell n = 295, dendritic cell Cd209a+ n = 542, dendritic cell Xcr1+ n = 302, dendritic cell Ccr7+ n = 119, dendritic cell cycling n = 83, dendritic cell activated MYCi n = 297, neutrophil n = 3771, neutrophil proinflammatory n = 1804, neutrophil activated MYCi n = 582, neutrophil MyD88 Trif KO n = 152, mast cell n = 41, erythrocyte n = 114, thrombocyte n = 97, B cell n = 2063, B cell memory n = 142, B1a cell n = 21, NK cell n = 381, NKT n = 344, naïve Cd8+ T cell n = 897, cytotoxic Cd8+ T cell n = 174, regulatory T cell n = 408, ɣδT cell n = 1373, ɣδT cell IFN n = 37, T cell cycling n = 128, ɣδT cell MYCi n = 477, hepatocyte n = 963, cholangiocyte n = 332. Boxplot defined as in Extended Data Fig. 1a. d, Boxplot showing number of transcripts expressed in each cell type, number of cells as in c. Boxplot defined as in Extended Data Fig. 1a. e, Boxplot showing number of genes detected in each cell type, which corresponds to the number of detected unique transcripts, number of cells as in c. Boxplot defined as in Extended Data Fig. 1a.
Extended Data Fig. 2 Cell abundance changes in acute liver failure and differences between APAP and TAA models.
a, Percentage of cell populations in control mice (n = 6), APAP (n = 8) and TAA (n = 6) treated mice, significance was determined using two-sided Wilcoxon test. Boxplot defined as in Extended Data Fig. 1a. Data points from SPF samples denoted as ●, GF - ■ and ABX - ▲ b, Heatmap showing differentially expressed genes in AAs between APAP and TAA treated mice. c, Heatmap showing differentially expressed genes in AAe between APAP and TAA treated mice. e, Violin plots showing normalised and scaled expression of example chemokines upregulated in activated Kupffer cells. d, Violin plots showing normalised and scaled expression of example chemokines, cytokines and extracellular matrix modifiers upregulated in activated endothelial cells. e, Violin plots showing normalised and scaled expression of example chemokines upregulated in activated Kupffer cells.
Extended Data Fig. 3 Receptors and ligands in ALF.
a, Boxplot showing percent of reads mapping to the mitochondrial genome in each cell type, number of cells as in Extended Data Fig. 1c.b, Boxplot showing normalised and scaled expression of Ccl2 receptor, Ccr2 in all cell types, number of cells as in Extended Data Fig. 1c.c, d, Baloon plots showing expression of (c) chemokines and cytokines and (d) their receptors.
Extended Data Fig. 4 Cellular states upon MYC inhibition.
a, Density plot of permutation analysis of number of MYC binding sites in randomly chosen 77 genes (black) in comparison to 77-gene signature (red) b Violin plots showing mild upregulation of expression of Myc in activated cells. c, Western blots of MYC and phospho-MYC and d quantification of phospho-MYC Western blot of control mice (n = 5), APAP (n = 5) and TAA (n = 5) treated mice. Boxplot defined as in Extended Data Fig. 1a. Significance was determined using two-sided Wilcoxon test. e, FACS gating strategy to identify Ly6C-positive monocytes. f, Barplot showing relative frequencies of cells in healthy and mice with ALF in the presence and absence of MYCi.
Extended Data Fig. 5 Cellular states upon MYC inhibition.
UMAP showing distribution of cell clusters in healthy, APAP and TAA treated mice in the presence and absence of MYCi.
Extended Data Fig. 6 Effect of MYC inhibition on gene expression.
a, b, Gene ontology term enrichment analysis of genes differentially expressed in healthy mice and healthy mice treated with MYCi in stellate cells and in Kupffer cells. GO analysis was performed with GProfiler using standard settings, p-values shown are corrected for multiple hypothesis testing using g:SCS algorithm. c, Volcanoplots showing differentially abundant genes healthy mice and healthy mice treated with MYCi. Y-axis value depicts multiple hypothesis testing corrected p-value calculated using DESeq2 package. d, e, Barplot showing infiltration of (d) Ly6C-positive monocytes and (e) neutrophils in the presence and absence of MYCi. Different colors of bars denote subpopulations of neutrophils; legend as in Extended Data Fig. 5. f–h, Boxplots showing expression of 77-gene signature in healthy mice, mice treated with APAP or TAA and mice treated with APAP and MYCi SPF (n = 3, cS=1999, cE=1463, cK=659), SPF + APAP (n = 4, cS=4339, cE=1517, cK=265), SPF + TAA (n = 4, cS=910, cE=1456, cK=285), in presence of MYCi: SPF + APAP + MYCi (n = 2, cS=251, cE=303, cK=125) and SPF + TAA + MYCi (n = 2, cS=198, cE=512, cK=233), *** denotes p-value < 0.001, n = number of mice, cS = number of stellate cells, cE = number of endothelial cells, cK = number of Kupffer cells. Boxplot defined as in Extended Data Fig. 1a. Significance was determined using one-sided Wilcoxon test. p-values in stellate cells: SPF + APAP vs SPF + APAP + MYCi 1.135⋅10−15, SPF + TAA vs SPF + TAA + MYCi 2.662⋅10−14; in endothelial cells: SPF + APAP vs SPF + APAP + MYCi 5.196⋅10−6, SPF + TAA vs SPF + TAA + MYCi 4.935⋅10−6; in Kupffer cells: SPF + APAP vs SPF + APAP + MYCi 1.287⋅10−8, SPF + TAA vs SPF + TAA + MYCi 1.517⋅10−7 (i) Violin plot showing normalised and scaled expression of Cdkn1a in three activated cells types. j, Gene ontology term enrichment analysis of genes differentially expressed in APAP and TAA treated mice with and without MYC inhibitor in stellate, endothelial and Kupffer cells. GO analysis was done as in Extended Data Fig. 6a-b.
Extended Data Fig. 7 Microbiome in acute liver failure.
a, PCA of 16 S microbiome ASV abundance data in the small intestine and in the colon of mice treated with APAP (intraperitoneal injection) and PBS control. b, Volcanoplots showing differential abundance analysis fold change and Benjamini-Hochberg adjusted p-values obtained with two-sided Wilcoxon test c, Alpha diversity metrics in control mice (colon n = 10, small intestine n = 10) and APAP treated mice (colon n = 9, small intestine n = 9), significance was determined using two-sided t-test. P-value for comparison between control and APAP treated mice for OTUs in the small intestine 0.3706, colon 0.0103, for evenness in the small intestine 0.04177, colon 0.04094, for Shannon diversity index in the small intestine 0.05235, colon 0.01271, for Faith’s phylogenetic diversity index in the small intestine 0.08351, colon 0.00511. Boxplot defined as in Extended Data Fig. 1a, ** denotes p-value < 0.01, * denotes p-value < 0.05. d, Box plots showing percent of cells, quiescent stellate cells and AAs within stellate cell populations, endothelial sinusoidal cells and AAe within endothelial cells and the Kupffer cells, AAk cells, monocytes and neutrophils within immune cells. GF n = 2, SPF n = 3, GF + APAP n = 2, ABX + APAP n = 2, SPF + APAP n = 4, GF + TAA n = 2, SPF + TAA n = 4. Boxplot defined as in Extended Data Fig. 1a.
Extended Data Fig. 8 Microbiome effect on cellular responses in acute liver failure.
a, Activity of hepatic enzyme aspartate aminotransferase (AST) and alanine transaminase (ALT) in serum in healthy germ free, antibiotics treated and specific pathogen free mice, significance was determined using one-sided Wilcoxon test; n = 9 for ABX and SPF, n = 10 for GF. Boxplot defined as in Extended Data Fig. 1a. b–e, Heatmaps showing differentially expressed genes between activated cells in GF APAP-induced and SPF APAP-induced mice. Heatmaps show expression of these genes in quiescent cells in healthy mice and in activated cells in mice treated with APAP, differentially expressed genes shown DESeq2 adjusted p-value <0.05.
Extended Data Fig. 9 TLR ligands in ALF.
a, b, Heatmap and boxplots showing mean levels of 655 nm absorbance in HEK-Blue TLR and NLR reporter cell lines subtracted with absorbance of corresponding Null cell line after application of portal serum from germ free (GF), antibiotics treated (ABX) and specific pathogen free (SPF) mice treated with APAP and TAA. Boxplot defined as in Extended Data Fig. 1a.
Extended Data Fig. 10 Cellular response to APAP in MyD88 Trif KO mice.
a, Relative frequencies of cells in healthy and mice with ALF in the presence and absence of MYCi as in Extended Data Fig. 4f and additionally in GF, ABX and MyD88 Trif-dKO mice. b, Gene ontology term enrichment analysis of genes in Kupffer cells significantly more abundant in wild type (top) and significantly more abundant in Myd88-Trif dKO (bottom). GO analysis was performed with GProfiler using standard settings, p-values shown are corrected for multiple hypothesis testing using g:SCS algorithm c-e, Violin plots showing normalised and scaled expression of key genes in activated stellate cells (top), activated endothelial cells (middle) and activated Kupffer cells (bottom) in wild type mice, in presence of MYCi and in MyD88-Trif dKO mice. f, Violin plots showing normalised and scaled expression of TLP2 coding gene Map3k8 in activated resident populations in presence and absence of MYC inhibition. g, Details of human liver samples including age in years, gender (F = female, M = male) and disease status.
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Kolodziejczyk, A.A., Federici, S., Zmora, N. et al. Acute liver failure is regulated by MYC- and microbiome-dependent programs. Nat Med 26, 1899–1911 (2020). https://doi.org/10.1038/s41591-020-1102-2
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DOI: https://doi.org/10.1038/s41591-020-1102-2
