Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE236424 | GEO | 2023/08/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Spatiotemporal hepatocyte heterogeneity impacts in vivo gene engineering [snRNA-Seq]

Project description:The liver is a central organ for metabolism and hepatocytes are 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. Here we investigate liver tissue dynamics in mice during growth and adulthood, by spatial transcriptomics, clonal analysis, and lineage tracing. We observe the progressive establishment of metabolic zonation of hepatocytes following weaning, with the specification of the centrilobular identity only in adults. We report that only a fraction of hepatocytes proliferate in the newborn liver, generating most of the adult tissue, and that preferential gene editing of the more proliferating hepatocytes allows expansion of the genetically engineered liver area. We also describe age-dependent differences in the efficiency and distribution of lentiviral in vivo gene delivery, with higher efficiency of gene transfer in young compared to adult animals and a skewed localization within the liver lobule. We identify high proteasome activity in the peri-central lobular area as the major determinant of the observed outcome and successfully revert it by proteasomal inhibition before vector administration. Overall, our findings provide new insights into the spatiotemporal dynamics of hepatocytes during post-natal growth, which extend our understanding of liver biology and have important implications for therapeutic applications.

2024-05-15 | GSE267146 | GEO

Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

Project description:The metabolic functions of the liver are organized spatially in a phenomenon known as zonation. This spatial organization of metabolic functions is linked to the differential exposure of central and portal hepatocytes to either systemic circulation or nutrient-rich blood afferent from the gastrointestinal tract, respectively. The mechanistic target of rapamycin complex 1 (mTORC1) is the central hub of a critical signaling pathway that links cellular metabolism to fluctuations in the levels of nutrients and insulin. To understand how these two signaling cues are integrated in the liver, we have generated mice with constitutive nutrient and insulin signaling to mTORC1 in hepatocytes (RragaGTP/fl; Tsc1fl/fl; Albumin-CreTg mice). Simultaneous activation of nutrient and hormone signaling to mTORC1 results in impaired establishment of the metabolic zonal identity of hepatocytes, a maturation process that takes place within the first weeks after birth. Mechanistically, a decrease in levels of the morphogenic pathway Wnt/β-catenin in hepatocytes and reduced expression of the Wnt2 ligand by liver endothelial cells after birth underlie this impaired wave of hepatocyte maturation. Lack of postnatal establishment of metabolic zonation of the liver is recapitulated in a model of constant supply of nutrients by total parenteral nutrition to neonatal pigs. Collectively, our work shows the critical role of hepatocyte sensing of fluctuations in nutrients and hormones after birth for triggering the latent metabolic zonation program.

2024-03-18 | PXD041439 | Pride

Comparative proteomic analysis of human liver tissue and isolated hepatocytes with a focus on proteins determining drug exposure

Project description:Freshly isolated human hepatocytes are considered the gold standard for in vitro studies of liver functions, including drug transport, metabolism, and toxicity. For accurate predictions of in vivo outcome, the isolated hepatocytes should reflect the phenotype of their in vivo counterpart, i.e., hepatocytes in human liver tissue. Here, we quantified and compared the membrane proteomes of freshly isolated hepatocytes and human liver tissue using a label-free shotgun proteomics approach. A total of 5144 unique proteins were identified, spanning over six orders of magnitude in abundance. There was a good global correlation in protein abundance. However, the expression of many plasma membrane proteins was lower in the isolated hepatocytes than in the liver tissue. This included transport proteins that determine hepatocyte exposure to many drugs and endogenous compounds. Pathway analysis of the differentially expressed proteins confirmed that hepatocytes are exposed to oxidative stress during isolation and suggested that plasma membrane proteins were degraded via the protein ubiquitination pathway. Finally, using pitavastatin as an example, we show how protein quantifications can improve in vitro predictions of in vivo liver clearance. We tentatively conclude that our data set will be a useful source for improved hepatocyte predictions of in vivo outcome.

2015-07-16 | PXD002235 | Pride

c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile-duct-ligation in mice

Project description:The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined yet. In order to better characterize the role of c-Met in hepatocytes we generated a hepatocyte-specific c-Met knockout mouse (c-MetM-bM-^HM-^Fhepa) using the Cre-loxP system and studied its relevance after bile-duct ligation. Two strategies for c-Met deletion in hepatocytes were tested. Early deletion during embryonic development was lethal, while post-natal Cre-expression was successful leading to the generation of viable c-MetM-bM-^HM-^Fhepa mice. Bile-duct ligation in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-MetM-bM-^HM-^Fhepa mice revealed a significant reduction of anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-MetM-bM-^HM-^Fhepa mice showed a stronger apoptotic response after bile-duct ligation and Jo-2 stimulation. This phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-a and IL-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-b1, a-SMA, collagen-1a mRNA expression and enhanced collagen-fiber staining in c-MetM-bM-^HM-^Fhepa mice. For gene array analysis c-MetDhepa and c-MetloxP/loxP controls were stimulated for 2 hours with 2M-BM-5g recombinant mouse HGF.Three animals per group were treated in parallel, before and after i.p. injection of recombinant HGF or NaCl.

2009-02-18 | E-GEOD-13992 | biostudies-arrayexpress

Hepatic gene expression in various different lots of chimeric mice with highly humanized liver

Project description:In addition to immunodeficiency, host mice for chimeric mice with highly humanized liver should have hepatic malfunction in order to allow higher replacement rate of human hepatocytes in the liver. Urokinase-type plasminogen activator (uPA) whole gene transfer is often employed to achieve hepatic malfunction in the host mice. We have established uPA cDNA transfer that is far stable, as compared with traditional whole uPA gene transfer. Hepatic gene expression was quite similar between whole uPA gene transfer and uPA cDNA transfer after transplantation of the same lot of human hepatocyte (BD195),, as compared with the variation of gene expression after transplantation of different lots of human hepatocytes to host mice with whole uPA gene transfer.

2015-06-17 | GSE69936 | GEO

c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile-duct-ligation in mice

Project description:The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined yet. In order to better characterize the role of c-Met in hepatocytes we generated a hepatocyte-specific c-Met knockout mouse (c-Met∆hepa) using the Cre-loxP system and studied its relevance after bile-duct ligation. Two strategies for c-Met deletion in hepatocytes were tested. Early deletion during embryonic development was lethal, while post-natal Cre-expression was successful leading to the generation of viable c-Met∆hepa mice. Bile-duct ligation in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-Met∆hepa mice revealed a significant reduction of anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-Met∆hepa mice showed a stronger apoptotic response after bile-duct ligation and Jo-2 stimulation. This phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-a and IL-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-b1, a-SMA, collagen-1a mRNA expression and enhanced collagen-fiber staining in c-Met∆hepa mice.

2009-02-18 | GSE13992 | GEO

Cholangiocytes contribute to hepatocyte regeneration after partial liver injury in larval zebrafish

Project description:Liver possesses robust regenerative ability, characterized by flexibility in the cellular source of regeneration based on the extent of the injury. After partial hepatectomy or minor injuries, hepatocytes, the primary liver cells, undergo self-duplication to replenish the liver mass. In contrast, when the damage is extensive, or hepatocyte proliferation is impaired, cholangiocytes contribute to hepatocyte recovery. This current paradigm of regenerative flexibility in the liver has been established for animals with little or no growth. However, the regenerative mechanisms during periods of growth in young animals remain unexplored. Here, we establish two new partial liver injury protocols in the zebrafish model of rapid growth during late larval stage and observe emergence of de novo hepatocytes in the presence of spared hepatocytes. Using single-cell RNA sequencing and lineage tracing, we identify cholangiocytes as the source of de novo hepatocytes. Our study offers a new perspective on the current paradigm of liver regenerating by proposing cholangiocyte-to-hepatocyte transdifferentiation as the default mechanism of hepatocyte recovery in late larval stage zebrafish.

2024-11-13 | GSE272484 | GEO

Liver gene expression in animals with hepatocyte-specific deletion of JAK2

Project description:Growth hormone signaling in hepatocytes is fundamentally important. Disruptions in this pathway have led to fatty liver and other metabolic abnormalities. Growth hormone signals through the JAK2/STAT5 pathway. Mice with hepatocyte specific deletion of STAT5 were previously shown to develop fatty liver. Our aim in this study was to determine the effect of deleting JAK2 in hepatocytes on liver gene expression. To do so, we generated animals with hepatocyte specific deletion of JAK2.

2011-05-01 | GSE26188 | GEO

Direct reprogramming of human fibroblasts to functional hepatocyte-like cells

Project description:Plasticity of differentiated cells has been proved by nuclear transfer, induced pluripotent cells and transdifferentiation. Here we show that by transduction of 3 factors (FOXA3, HNF1A and HNF4A), human fetal fibroblasts can be converted to hepatocyte-like cells (hiHep cells), expressing hepatic marker genes, and acquiring many mature hepatocyte functions in vitro and in vivo. Human fetal fibroblasts (HFF) were tranfected with 3 liver enriched transcription factors (FOXA3, HNF1A, HNF4A), and converted to hepatocyte-like cells (hiHep cells). HFF and primary human hepatocytes (PHH) serve as control.

2014-03-06 | E-GEOD-42643 | biostudies-arrayexpress

A comprehensive transcriptomic comparison of hepatocyte model systems

Project description:We generated intrahepatic cholangiocyte organoids and fetal hepatocyte organoids to compare their transcriptomic profile with liver tissue, primary human hepatocytes, and other hepatocyte model systems.

2022-09-25 | GSE214097 | GEO

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