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Periportal macrophages protect against commensal-driven liver inflammation

ABSTRACT: The liver is the main gateway from the gut and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zonation, such as peri-portal vein (PV) and peri-central vein (CV) zones; however, the functional and molecular differences among liver macrophages in these zones remain poorly understood. Here, intravital multiphoton imaging revealed significantly suppressed in PV zones. Zonation-specific single-cell transcriptome analyses detected an immuno-suppressive macrophage subset highly expressing IL-10 and Marco, a scavenger receptor, enriched in PV zones. Inhibited IL-10 signaling and Marco-deficient conditions impaired the suppressive function of these macrophages. The reduced number of Marco-positive suppressive macrophages in germ-free or antibiotic-treated conditions suggested that gut commensal bacteria were responsible for inducing this specific population. Dextran sulfate sodium-induced colitis led to inflammation in liver PV zones, which was more prominent under Marco-deficient conditions. Marco-positive inflammatory macrophages in the human liver are diminished in primary sclerosing cholangitis (PSC), an intractable disease characterized by chronic inflammation around the portal veins and bile ducts. Collectively, commensal bacteria and their pathogenic substances induce Marco-positive immunosuppressive macrophages, consequently limiting excessive inflammation in PV zones. Failure of this self-limiting system may cause hepatic inflammatory disorders, such as PSC.

ORGANISM(S): Mus musculus

PROVIDER: GSE213165 | GEO | 2024/03/06

REPOSITORIES: GEO

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Periportal macrophages protect against commensal-driven liver inflammation [spatial transcriptomics]

Project description:The liver is the main gateway from the gut and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zonation, such as peri-portal vein (PV) and peri-central vein (CV) zones; however, the functional and molecular differences among liver macrophages in these zones remain poorly understood. Here, intravital multiphoton imaging revealed significantly suppressed in PV zones. Zonation-specific single-cell transcriptome analyses detected an immuno-suppressive macrophage subset highly expressing IL-10 and Marco, a scavenger receptor, enriched in PV zones. Inhibited IL-10 signaling and Marco-deficient conditions impaired the suppressive function of these macrophages. The reduced number of Marco-positive suppressive macrophages in germ-free or antibiotic-treated conditions suggested that gut commensal bacteria were responsible for inducing this specific population. Dextran sulfate sodium-induced colitis led to inflammation in liver PV zones, which was more prominent under Marco-deficient conditions. Marco-positive inflammatory macrophages in the human liver are diminished in primary sclerosing cholangitis (PSC), an intractable disease characterized by chronic inflammation around the portal veins and bile ducts. Collectively, commensal bacteria and their pathogenic substances induce Marco-positive immunosuppressive macrophages, consequently limiting excessive inflammation in PV zones. Failure of this self-limiting system may cause hepatic inflammatory disorders, such as PSC.

2024-03-06 | GSE213388 | GEO

Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis

Project description:We profile the transcriptomes of ~30,000 mouse single cells to deconvolve the hepatic mesenchyme in healthy and fibrotic liver at high resolution. We reveal spatial zonation of hepatic stellate cells across the liver lobule, designated portal vein-associated HSC and central vein-associated HSC, and uncover an equivalent functional zonation in a mouse model of centrilobular fibrosis. Our work illustrates the power of single-cell transcriptomics to resolve key collagen-producing cells driving liver fibrosis with high precision.

2019-11-01 | GSE137720 | GEO

Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics

Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently induces the development of hepatic fat accumulation and inflammation with fibrosis in mice initially in the portal region. Conversely, differential gene and protein expression is first detected in the central region. To further investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing and spatial transcriptomics were used for livers of male mice gavaged with TCDD every 4 days for 28 days. The proportion of 11 cell (sub)types across 131,613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1,339 (macrophages) differentially expressed genes. Spatial analyses revealed initial loss of portal identity that eventually spanned the entire liver lobule with increasing dose. Induction of R-spondin 3 (Rspo3) and pericentral Apc, suggested dysregulation of the Wnt/β-catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies.

2022-10-21 | GSE206294 | GEO

Congestion enriches intra-hepatic macrophages through reverse zonation of CXCL9 in liver sinusoidal endothelial cells

Project description:Background & Aims Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid which contribute to congestive fibrosis and portal hypertension (PHTN). Methods To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor. Results Peri-central macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs which promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNANish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that -catenin and hypoxia inducible factor-1α regulate CXCL9 transcription in peri-central LSECs. Conclusions CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD.

2024-01-27 | GSE253915 | GEO

Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

Project description:The metabolic functions of the liver are organized spatially in a phenomenon known as zonation. This spatial organization of metabolic functions is linked to the differential exposure of central and portal hepatocytes to either systemic circulation or nutrient-rich blood afferent from the gastrointestinal tract, respectively. The mechanistic target of rapamycin complex 1 (mTORC1) is the central hub of a critical signaling pathway that links cellular metabolism to fluctuations in the levels of nutrients and insulin. To understand how these two signaling cues are integrated in the liver, we have generated mice with constitutive nutrient and insulin signaling to mTORC1 in hepatocytes (RragaGTP/fl; Tsc1fl/fl; Albumin-CreTg mice). Simultaneous activation of nutrient and hormone signaling to mTORC1 results in impaired establishment of the metabolic zonal identity of hepatocytes, a maturation process that takes place within the first weeks after birth. Mechanistically, a decrease in levels of the morphogenic pathway Wnt/β-catenin in hepatocytes and reduced expression of the Wnt2 ligand by liver endothelial cells after birth underlie this impaired wave of hepatocyte maturation. Lack of postnatal establishment of metabolic zonation of the liver is recapitulated in a model of constant supply of nutrients by total parenteral nutrition to neonatal pigs. Collectively, our work shows the critical role of hepatocyte sensing of fluctuations in nutrients and hormones after birth for triggering the latent metabolic zonation program.

2024-03-18 | PXD041439 | Pride

miRNA expression in spatially-sorted hepatocytes

Project description:The mammalian liver is composed of repeating hexagonal units termed lobules. Spatially-resolved single-cell transcriptomics revealed that about half of hepatocyte genes are differentially expressed across the lobule. Technical limitations impede reconstructing similar global spatial maps of other hepatocyte features. Here, we used zonated surface markers to sort hepatocytes from defined lobule zones with high spatial resolution. We applied transcriptomics, miRNA array measurements and Mass spectrometry proteomics to reconstruct spatial atlases of multiple zonated hepatocyte features. We found that protein zonation largely overlapped mRNA zonation, with the periportal HNF4α as an exception. We identified zonation of miRNAs such as miR-122, and inverse zonation of miRNAs and their hepatocyte target genes, implying potential regulation through zonated mRNA degradation. These targets included the pericentral Wnt receptors Fzd7 and Fzd8 and the periportal Wnt inhibitors Tcf7l1 and Ctnnbip1. Our approach facilitates reconstructing spatial atlases of multiple cellular features in the liver and other structured tissues.

2019-07-26 | GSE134827 | GEO

DRAGON 1- Training, Accreditation, Implementation and Safety Evaluation of Combined PVE/HVE

Project description:Brief Summary: Some colorectal liver metastases can only be resected after inducing liver regeneration by portal vein embolization (PVE) to increase size function of the future liver remnant (FLR). While PVE is standard, embolization of portal vein and hepatic veins (PVE/HVE) on one side of the liver may faster and more extensive liver size and function growth. PVE/HVE is a novel procedure and requires a safety and feasibility evaluation in a pretrial (DRAGON1) to then be compared in a randomized controlled trial (RCT) to PVE (DRAGON 2).

| 2330366 | ecrin-mdr-crc

Transcriptional profiles of liver lobular zones from non-pregnant mice and pregnant mice at dpc8 and dpc16.

Project description:We report transcriptional profiles of each liver lobular zone from non-pregnant mice and pregnant mice at dpc8 and dpc16. By RNA-sequencing of LCM-isolated each zonal cells, we revealed that genes related to actin cytoskeleton, extracellular matrix organization and vascularization were enriched in the PA (zone2) and CV (zone3) zones at dpc8 and cell division related genes were enriched in the PV (zone1) zone at dpc8. At dpc16, genes related to metabolism, catabolism and xenobiotic process were enriched in all zones.

2023-12-13 | GSE181874 | GEO

Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis

Project description:Based on the identification of a transcriptomic signature, including Slit2, characterizing portal mesenchymal stem cells (PMSC) and derived myofibroblast (MF), we examined the gene expression profile of in liver tissue derived from multiple human liver disorders, including primary sclerosing cholangitis (PSC) (n=12), non-alcoholic steatohepatitis (NASH) (n=7) and other liver diseases (i.e., primary biliary cholangitis, autoimmune hepatitis, alcoholic liver disease and haemochromatosis) (n=8) and compared them to healthy controls (tumor free tissue from livers with metastasis from colorectal cancer) (n=5). We found that SLIT2 was overexpressed in the liver of patients with NASH, PSC and other chronic liver diseases. We also examined the microarray data of the human liver tissue samples for the transcriptomic signatures and found that in the different types of liver diseases the gene signature of PMSCs/PMSC-MFs was increased compared to normal liver, and correlated with the expression of ACTA2, COL1A1 and vWF.

2020-10-21 | GSE159676 | GEO

Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker

Project description:Macrophages are the most common infiltrating immune cells in glioblastoma (GBM), and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood. Here, we combine new and previously-published single-cell RNA-seq data from 86,279 single cells from a total of 63 gliomas to profile 17,774 individual macrophages. Unsupervised clustering revealed an anti-inflammatory subpopulation of macrophages characterized by expression of MARCO (macrophage receptor with collagenous structure), a gene which has not been previously well-characterized in gliomas. MARCO is almost exclusively expressed in macrophages of IDH1-wildtype GBM rather than IDH1-mutated GBM or lower-grade gliomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small-cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis in TCGA glioblastomas, and associates with the mesenchymal expression subtype. Our single-cell analysis shows that this previously-reported mesenchymal signature primarily arises from MARCO-expressing macrophages. These MARCO-expressing macrophages differentially over-express gene sets related to hypoxia and the epithelial-mesenchymal transition, and under-express gene sets related to inflammation and antigen presentation. We show evidence that MARCO-expressing macrophages are recruited from the blood (as opposed to being resident microglia), and paired single-cell analysis of tumor and myeloid cells demonstrate that this recruitment may be driven by known chemoattractant factors. Furthermore, MARCO expression is significantly altered over the course of treatment with PD1 checkpoint inhibitors. These findings illustrate a novel myeloid subpopulation that drives tumor progression in glioblastomas, and suggest potential therapeutic targets to prevent their recruitment glioblastoma.

2020-12-23 | GSE141383 | GEO

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