Project description:To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to to study the genes that change in the progress of human liver fibrosis, so as to provide a basis for the clinical treatment of liver fibrosis.
Project description:Persistent liver injury triggers a fibrogenic program that causes pathologic remodelling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and regression remain understudied. Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key liver disease readouts, such as portal pressure, collagen proportionate area, and transaminase serum levels, to most differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. These candidate biomarkers (e.g., Scube1, Tcf4, Src, Hmga1, Trem2, Mafk, Mmp7) were also validated in RNA-seq datasets of patients with cirrhosis and portal hypertension. Finally, deconvolution analysis identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area in both models.
Project description:Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis.Through multi-modal data integration,we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory from hepatocytes to cholangiocytes associated with disease remodelling.We identifypro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach providesa spatial atlas of gene regulation and defines molecular signatures associated liver diseasefor targeted therapeutics or as early diagnostic markers of progressive liver disease. This is the snRNA-seq data for the work.
Project description:Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis.Through multi-modal data integration,we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory from hepatocytes to cholangiocytes associated with disease remodelling.We identifypro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach providesa spatial atlas of gene regulation and defines molecular signatures associated liver diseasefor targeted therapeutics or as early diagnostic markers of progressive liver disease. This is the snATAC-seq data for the work.
Project description:Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis.Through multi-modal data integration,we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory from hepatocytes to cholangiocytes associated with disease remodelling.We identifypro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach providesa spatial atlas of gene regulation and defines molecular signatures associated liver diseasefor targeted therapeutics or as early diagnostic markers of progressive liver disease. This is the 10X Visium data for the work.
Project description:Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis.Through multi-modal data integration,we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory from hepatocytes to cholangiocytes associated with disease remodelling.We identifypro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach providesa spatial atlas of gene regulation and defines molecular signatures associated liver diseasefor targeted therapeutics or as early diagnostic markers of progressive liver disease. This is the 10X Visium data for the work.