Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography
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PROVIDER: PRJNA820030 | ENA |
REPOSITORIES: ENA
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Project description:The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of beta-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of beta-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
2022-09-01 | GSE199463 | GEO
Project description:Purpose: To determine transcriptome profile of the facial processes of Wnt9b, Rspo2 and double gene knockout embryos by NG RNA sequencing Method: Embryonic facial process RNA samples isolated from wild type, Rspo2, Wnt9b and Rspo2;Wnt9b double mutants in triplicate (except wild type (n=2)) at embryonic day 10.5 Results: single-end 50bp reads, 19.8 million reads - 30.7 million reads.
2020-03-25 | GSE147474 | GEO
Project description:The Wolffian or mesonephric duct is the embryonic primordium that gives rise to the epididymis, vas deferens and seminal vesicle. The androgen action in the Wolffian duct mesenchyme during fetal development is the predominant driver for Wolffian duct maintenance which is critical for male fertility. However, the androgen’s capability of promoting Wolffian duct maintenance was completely lost in the absence of Wnt9b in mice. In this study, we followed up with this interesting phenomenon and elucidated cellular and molecular mechanisms whereby Wnt9b facilitates Wolffian duct maintenance in male embryos. Wnt9b belongs to the WNT family of secreted proteins and is expressed in the Wolffian duct epithelium. We found that the Wolffian duct degeneration in Wnt9b-/- male embryos was accompanied with decreased cell proliferation in the epithelium but not in the mesenchyme during sexual differentiation. Wnt9b deletion did not impair testicular androgen synthesis but altered expression pattern of mesenchymal androgen receptor. The percentage of androgen receptor positive cells in the mesenchyme was significantly reduced, which can be the cause of decreased epithelial proliferation. Wnt9b actions can be transduced by both β-catenin-dependent and β-catenin-independent pathways in the context of target cells. Transcriptomic analysis of E12.5 Wnt9b+/+ and Wnt9b-/- mesonephroi revealed that expression of multiple WNT/β-catenin-target genes was reduced in the absence of Wnt9b. Deletion of mesenchymal β-catenin led to caudal Wolffian duct degeneration and cystic formation in the cranial region. Taken together, our study uncovers the important WNT9B-AR signaling axis mediating the epithelial-mesenchymal interaction in Wolffian duct development.
2024-12-31 | GSE282202 | GEO
Project description: Not available
| S-EPMC9588996 | biostudies-literature
Project description:Wnt9b is expressed in the ureteric bud of the kidney at all stages of development. In Wnt9b mutants, the ureteric bud forms but the metanephric mesenchyme is never induced to undergo differentiation. We used microarrays to compare differences in gene expression between wildtype and Wnt9b mutants. To focus on direct targets, mesenchymes isolated away from the E11.5 ureteric bud were assayed
2017-10-26 | GSE106195 | GEO
Project description:The widespread adoption of single-cell proteomics (SCP) in biology has been limited by complex workflows and reliance on specialized instrumentation. Here we present EasySCP, a high-throughput and lossless method that integrates FACS-based single-cell sorting, an all-in-one, single-step digestion process in 384-well plates, and sensitive mass spectrometry. EasySCP identifies nearly 5,000 proteins from individual HEK293 cell. Applied to murine liver, EasySCP achieved spatially resolved proteomics profiling of hepatocytes zonation, detecting an average of 3,500 proteins per hepatocyte and uncovering zonation patterns for 3,277 out of 5,267 proteins, representing unprecedented depth and coverage in single-cell liver proteomics. Building on 215 conserved zonation markers, we further developed hepatocyte spatial status score (HSS) that enables accurately reconstruct liver zonation across single-cell and spatial multi-omics datasets. Together, our study introduces EasySCP, a broadly accessible tool for dissecting cellular heterogeneity at single-cell proteomics resolution in both healthy and disease states, effectively bridging the gap between transcriptomics and functional proteomics.
2026-05-06 | PXD070185 | Pride
Project description:Transcriptome analysis of the facial processes in Rspo2, WNT9b and Rspo2 Wnt9b double mutant mice
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Project description:The widespread adoption of single-cell proteomics (SCP) in biology has been limited by complex workflows and reliance on specialized instrumentation. Here we present EasySCP, a high-throughput and lossless method that integrates FACS-based single-cell sorting, an all-in-one, single-step digestion process in 384-well plates, and sensitive mass spectrometry. EasySCP identifies nearly 5,000 proteins from individual HEK293 cell. Applied to murine liver, EasySCP achieved spatially resolved proteomics profiling of hepatocytes zonation, detecting an average of 3,500 proteins per hepatocyte and uncovering zonation patterns for 3,277 out of 5,267 proteins, representing unprecedented depth and coverage in single-cell liver proteomics. Building on 215 conserved zonation markers, we further developed hepatocyte spatial status score (HSS) that enables accurately reconstruct liver zonation across single-cell and spatial multi-omics datasets. Together, our study introduces EasySCP, a broadly accessible tool for dissecting cellular heterogeneity at single-cell proteomics resolution in both healthy and disease states, effectively bridging the gap between transcriptomics and functional proteomics.
2026-05-06 | PXD074900 | Pride
Project description:The widespread adoption of single-cell proteomics (SCP) in biology has been limited by complex workflows and reliance on specialized instrumentation. Here we present EasySCP, a high-throughput and lossless method that integrates FACS-based single-cell sorting, an all-in-one, single-step digestion process in 384-well plates, and sensitive mass spectrometry. EasySCP identifies nearly 5,000 proteins from individual HEK293 cell. Applied to murine liver, EasySCP achieved spatially resolved proteomics profiling of hepatocytes zonation, detecting an average of 3,500 proteins per hepatocyte and uncovering zonation patterns for 3,277 out of 5,267 proteins, representing unprecedented depth and coverage in single-cell liver proteomics. Building on 215 conserved zonation markers, we further developed hepatocyte spatial status score (HSS) that enables accurately reconstruct liver zonation across single-cell and spatial multi-omics datasets. Together, our study introduces EasySCP, a broadly accessible tool for dissecting cellular heterogeneity at single-cell proteomics resolution in both healthy and disease states, effectively bridging the gap between transcriptomics and functional proteomics.
2025-10-30 | PXD070083 |
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