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Sepsis-induced changes in hepatic cell communication in mice: RNA-seq on purified cells

ABSTRACT: Sepsis, which affects 49 million people yearly, killing 11 million of them, involves activation of inflammation, as well as significant metabolic reprogramming. The liver is affected by these changes and is confronted with pathogens and is a key organ in restoring homeostasis. We addressed the question to what extent cell-cell communication between hepatic cell types is affected in sepsis, using the CLP model of sepsis in mice. We sorted the four major hepatic cell types, hepatocytes (HEPs), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) as well as non-KC CD45+ cells and performed bulk deep RNAseq. Cell-specific pathways were studied, and we focused on cell-cell interactions between the cell types. We found that HSCs, which in control (Sham) animals are not significantly communicative, in sepsis behave as the major signal-spreading cell type, primarily stimulated by LSECs. The impact of the HSC signals on the other cell types was investigated by NicheNet and reveals interesting new insights into the initiation of diverse hepatic responses in sepsis, such as pathogen clearance, ECM remodeling, chemotaxis and metabolic reprogramming. HSCs may therefore be considered as primary cells to targets in sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE311736 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background & Aims: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis. Methods: Endothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. Results: POFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. Conclusions: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.

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Sepsis-induced changes in hepatic cell communication in mice: RNA-seq on purified cells

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