Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Clonal dynamics of normal hepatocyte expansions in homeostatic human livers and their association with the biliary epithelium

ABSTRACT: The majority of human liver research is disease-focused such that far less is known of cellular dynamics within morphologically normal human liver. We have leveraged cytochrome c oxidase deficiency as a marker of clonal hepatocyte populations in such tissues. We demonstrate these populations commonly associate with portal tracts and lineage-trace hepatocytes with cholangiocytes, indicating the presence of a bipotential common ancestor at this niche. We also observe rare periportal SOX9+ hepatocytes progenitor candidates in our human tissues. To understand clonal expansion dynamics, we measured methylation diversity and identified mtDNA variants by next-generation sequencing within spatially-defined clonal hepatocyte patches. We coupled our sequencing with mathematical modelling and Bayesian inference to compare spatial patterns of mtDNA variants under assumptions with or without faster expansion from a portal-associated niche. These datasets support the existence of a periportal progenitor niche and indicate that clonal patches slowly expand, perhaps due to acute environmental stimuli, then quiesce. These findings crucially contribute to our limited understanding of hepatocyte dynamics in normal human liver and provide a baseline for further understanding how they may be modulated in diseased liver.

PROVIDER: EGAS00001005539 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

RNA sequencing of CCO- and CCO+ human hepatocytes

Project description:RNAseq data from Passman et al 2023. Clonal CCO-deficient hepatocyte patches and nearby CCO-proficient hepatocytes were identified in morphologically normal human livers and sampled at varying distances along the PT-CV axis. Samples are named according to their location within the liver lobule, with "PT" denoting samples abutting the portal triad, "CV" denoting samples abutting the central hepatic vein, and "Mid" sampled acquired midway between these structures. Normal human liver is thought to be generally quiescent, however clonal hepatocyte expansions have been observed but neither their cellular source nor their expansion dynamics have been determined. Knowing the hepatocyte cell of origin, and their subsequent dynamics and trajectory within the human liver will provide an important basis to understand disease-associated dysregulation. Here we use in vivo lineage tracing and a combination of methylation sequence analysis to demonstrate normal human hepatocyte ancestry. We exploit next generation mitochondrial sequencing to determine hepatocyte clonal expansion dynamics across spatially-distinct areas of laser-capture microdissected clones, in tandem with computational modelling in morphologically-normal human liver.

| EGAS00001006984 | EGA

0bf3ef30-d3f9-47cb-8c57-75d5c62c7306 - samples

Project description:BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. CCO-proficient hepatocytes acquired from human livers in which clonal CCO-deficient hepatocyte patches had been previously identified. Individual BAM files are named according to their patch, line and sample location, where PT denotes tissue near to the portal triad (PT), central hepatic vein (CV) and midway between these two structures (Mid). "Stroma" control samples were used for identifying germ-line variants. Sequenced on NextSeq 500 platform.

| EGAD00001010016 | EGA

Clonal dynamics of normal hepatocyte expansions in homeostatic human livers and their association with the biliary epithelium

Project description:BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. CCO-proficient hepatocytes acquired from livers in which clonal CCO-deficient hepatocyte patches had been previously identified. Individual BAM files are named according to their patch, line and sample location, where PT denotes tissue near to the portal triad (PT), central hepatic vein (CV) and midway between these two structures (Mid). "Stroma" control samples were used for identifying germ-line variants. Sequenced on NextSeq 500 platform.

| EGAS00001006962 | EGA

f5a3bc98-8b28-4a25-8b6d-5f10ef0fce80 - samples

Project description:BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. Clonal CCO-deficient patches of hepatocytes were identified in human liver samples, and samples were taken along a line spanning approximately from the portal triad to the central hepatic vein. Individual BAM files are named according to their patch, line and cut, where cut 1 is nearest to the portal triad, and cuts 2, 3 etc. lying further from the portal triad. Other file types include "Bulk" samples, contain sequencing data of the remaining CCO-deficient cells that were not sampled as part of the line of cuts, and "Stroma" control samples (used for identifying germ-line variants). Sequenced on NextSeq 500 platform.

| EGAD00001007991 | EGA

Transcriptomic signatures of progressive and regressive liver fibrosis and portal hypertension

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.

2024-02-13 | E-MTAB-13804 | biostudies-arrayexpress

364ac256-2092-4b42-bb6c-c36cd70e79aa - samples

| EGAD00001010033 | EGA

Spatiotemporal hepatocyte heterogeneity impacts in vivo gene engineering [Visium Spatial Transcriptomics]

Project description:The liver is a central organ for physiology and metabolism, with hepatocytes being the main cell type responsible for most of its functions. Several previous studies investigated the cell types involved in tissue homeostasis and regeneration, however the mechanisms underlying post-natal liver growth and establishment of the mature hepatocyte phenotypes remain to be fully understood. Moreover, genetic modification of hepatocytes is emerging as a promising therapeutic approach, particularly for genetic diseases of the coagulation system and hepatic metabolism. Here, we investigate liver tissue dynamics in mice during post-natal growth and turnover in adulthood, by spatial transcriptomics, clonal analysis, and lineage tracing. We observe progressive establishment of metabolic zonation of hepatocytes and that only a fraction of hepatocytes proliferates in the newborn liver, generating most of the adult tissue. We assess the impact of these changes on both in vivo liver gene transfer and gene editing. We show that the age at treatment affects both the efficiency and lobule distribution of lentiviral vector-mediated gene transfer, and that preferential targeting of the more proliferating hepatocytes allows expansion of the genetically modified liver area. Overall, our findings provide new insights into the spatio-temporal dynamics of the liver during post-natal growth and hepatocyte heterogeneity, with broad implications for liver biology and therapeutic applications.

2023-08-01 | GSE236424 | GEO

Identification of a portal vessel-associated fetal liver hematopoietic stem cell niche

Project description:Whereas the cellular basis of the hematopoietic stem cell (HSC) niche in the bone marrow has been characterized, the nature of the fetal liver (FL) niche is not yet elucidated. We show that Nestin+NG2+ pericytes associate with portal vessels, forming a niche promoting HSC expansion. Nestin+NG2+ cells and HSCs scale during development with the fractal branching patterns of portal vessels, tributaries of the umbilical vein. After closure of the umbilical inlet at birth, portal vessels undergo a transition from Neuropilin-1+Ephrin-B2+ artery to EphB4+ vein phenotype, associated with a loss of peri-portal Nestin+NG2+ cells and emigration of HSCs away from portal vessels. These data support a model in which HSCs are titrated against a peri-portal vascular niche with a fractal-like organization enabled by placental circulation. Characterization of the transcriptome of fetal liver and adult bone marrow niche using RNA-seq

2015-12-03 | E-GEOD-72341 | biostudies-arrayexpress

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Project description:The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.

2024-11-14 | PXD051593 | Pride

LC-MS/MS of mouse hepatocytes sorted by lobule layers

Project description:Hepatocytes of the mammalian liver are organized in liver lobules and operate in a spatially-dependent manner. Cells in different positions along the lobule’s porto-cenrtal axis, defined by the directionality of blood flow, express different genes and perform different liver tasks. Gradients of the transcriptome along liver lobule axis has been recently established, yet not for the hepatocyte proteome. We used two surface markers whose levels are inversely zonated – CD73 with a decreasing gradient from pericentral to periportal hepatocytes and E-cadherin with increasing gradient from portal to central hepatocytes. By staining for both surface markers, we efficiently isolated bulk populations of hepatocytes from distinct lobule layers by Fluorescence Activated Cell Sorting (FACS). Over all, we sorted 100,000 hepatocytes from each of eight spatially distinct populations, from five different mice. Cells were washed, digested by trypsin and subjected to LC-MS/MS. More cells from same populations from the same mice were also collected for mRNA sequencing and microRNA microarray profiling, to achieve a multi-omic view on spatially sorted hepatocytes, for better understanding of the transcriptomic and post-transcriptomic levels of regulation of liver zonation.

2019-08-06 | PXD014512 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data