Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA566389 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10145300.fastq.gz | Fastqsanger.gz | |||
| SRR10145400.fastq.gz | Fastqsanger.gz | |||
| SRR10145500.fastq.gz | Fastqsanger.gz | |||
| SRR10145600.fastq.gz | Fastqsanger.gz | |||
| SRR10145700.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 2368 |
Similar Datasets
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
Project description:Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.
| S-EPMC6856722 | biostudies-literature
Project description:Hepatic stellate cells (HSCs) exert a central pathogenic role in the development of liver fibrosis. However, the fibrosis-independent and homeostatic functions of these specialized liver pericytes remain poorly understood. Here, we demonstrate that genetic depletion of HSCs alters Wnt target gene expression in hepatocytes and liver zonation, leading to profound alterations of regeneration, cytochrome P450 metabolism and injury. HSC-selective deletion of Rspondin-3, a modulator of Wnt signalling with high enrichment in HSCs, phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, regeneration and cytochrome P450-mediated detoxification and increases alcohol-associated and metabolic dysfunction-associated steatotic liver injury. Rspondin-3 expression decreases with HSC activation and is associated with disease progression in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These hitherto unknown protective and hepatocyte-regulating functions of HSCs via Rspondin-3, resembling the R-spondin-expressing stromal niche of other organs, should be integrated into therapeutic concepts for liver fibrosis.
2025-03-03 | GSE256398 | GEO
Project description:Hepatic stellate cells (HSCs) exert a central pathogenic role in the development of liver fibrosis. However, the fibrosis-independent and homeostatic functions of these specialized liver pericytes remain poorly understood. Here, we demonstrate that genetic depletion of HSCs alters Wnt target gene expression in hepatocytes and liver zonation, leading to profound alterations of regeneration, cytochrome P450 metabolism and injury. HSC-selective deletion of Rspondin-3, a modulator of Wnt signalling with high enrichment in HSCs, phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, regeneration and cytochrome P450-mediated detoxification and increases alcohol-associated and metabolic dysfunction-associated steatotic liver injury. Rspondin-3 expression decreases with HSC activation and is associated with disease progression in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These hitherto unknown protective and hepatocyte-regulating functions of HSCs via Rspondin-3, resembling the R-spondin-expressing stromal niche of other organs, should be integrated into therapeutic concepts for liver fibrosis.
2025-03-03 | GSE256377 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating genes in perivenous hepatocytes, while suppressing genes in their periportal counterparts. The understanding of liver gene zonation and zonation regulators in disease was limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combination of spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt target gene expression level and zonation spatial pattern were in line with the upregulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control livers, whereas expanded to the periportal zone in NASH livers. AAV8-mediated RSPO3 overexpression in controls resulted in a zonation change, and further amplified the disturbed zonation of Wnt target genes in NASH, but had no impacts on steatosis, inflammation and fibrosis. In summary, our study demonstrated the alteration of Wnt signaling in a mouse NASH model, leading to perturbed liver zonation.
2024-08-01 | GSE248077 | GEO
Project description:Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis
| PRJNA430822 | ENA
Project description:To identify proteins phosphorylated by Akt downstream of PI3K-mediated PDGFRalpha signaling, we immunoprecipitated Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates and analyzed the peptides by nano LC-MS/MS.
2019-06-04 | PXD000779 | Pride
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110673 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110672 | GEO
Project description:Kidney fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. Aimed at unraveling disease mechanisms and identifying potential therapeutic targets, this study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells. Using computational network modeling we integrated transcriptomics, proteomics, phosphoproteomics, and secretomics with imaging of the extracellular matrix (ECM). We quantified over 14,000 biomolecules across seven time points following TGF-β stimulation, revealing distinct temporal patterns in the expression and activity of known and potential novel renal fibrosis markers and modulators. The resulting time-resolved multi-omic network models allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and elucidated regulatory mechanisms underlying kidney fibrosis. Notably, we demonstrate that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a valuable resource for the organ fibrosis research community.
2024-11-07 | E-MTAB-14521 | biostudies-arrayexpress