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Oval cells from DDB1 mutant mouse

ABSTRACT: Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the locazation, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, enriched in oval cells. This genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE31588 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA145605

REPOSITORIES: GEO

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Oval cells from DDB1 mutant mouse

Project description:Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the locazation, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, enriched in oval cells. This genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer. Total RNA obtained from isolated EpCAM+ cells from DDB1 mutant mice compared to wild type hepatocytes

2012-01-01 | E-GEOD-31588 | biostudies-arrayexpress

FBP1 loss disrupts liver metabolism and promotes tumourigenesis through a hepatic stellate cell senescence secretome

Project description:Crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, and consequent effects on liver tumourigenesis, are incompletely understood. We show here that hepatocyte specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours, and hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype (SASP). Depleting senescent HSCs by senolytic treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, subsequent SASP development, and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical link between hepatocyte metabolism and HSC senescence that promotes tumour growth.

2020-03-02 | MSV000085045 | MassIVE

Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation

Project description:Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.

2023-06-27 | GSE211370 | GEO

The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

Project description:Hematopoietic stem cells (HSC) are regulated to keep the balance between self-renewal and differentiation. However, little is known about post-translational regulations in HSCs. In this study, we characterize the role of DDB1, a component of the Cul4A-DDB1 E3 ubiquitin ligase complex, in HSCs and progenitors by using conditional DDB1 knockout models. We show that the maintenance and differentiation of both adult and fetal HSCs and progenitor cells is dependent on DDB1 function. Deletion of DDB1 alters cell cycle progression and induces apoptosis. Furthermore, deletion of DDB1 in developing thymocytes had no effects on T cell differentiation, whereas DDB1-deficient peripheral T cells were not able to enter cell cycle when stimulated in vitro. In addition, DDB1 is essential for T cell leukemia initiation. Our results reveal that DDB1 is required for adult and fetal hematopoiesis as it controls progenitor and stem cell homeostasis. Transcriptional consequences of inactivating DDB1 in fetal LSK cells. Four samples were analyzed: wild-type (WT) control and DDB1-deficient (DDB1) Lin-ckit+Sca1+ (LSK) cells sorted from fetal livers E16.5 of DDB1 flox/flox, VavCre+ and control mice.

2015-07-10 | E-GEOD-70658 | biostudies-arrayexpress

Human hepatic stellate cell-derived extracellular vesicles LC-MSMS

Project description:Activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition are characteristics of liver fibrosis. Several studies have shown the importance of hepatocyte and endothelial cell-derived extracellular vesicles (EVs) in liver pathobiology. However, less is known about the role of HSC-derived EVs in liver diseases. In this study, we investigated the molecules released through HSC-derived EVs and whether these can promote fibrosis.

2018-10-18 | PXD007258 | Pride

The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

2015-07-10 | GSE70658 | GEO

A New Liver-Regeneration Molecular Mechanism Involving Hepatic Stellate Cells, Kupffer Cells, and Glucose-Regulated Protein 78 as a New Hepatotrophic Factor

Project description:Background and aims: Lethal liver failure is an important clinical issue. To overcome liver failure, we focused on liver regeneration mechanisms by activation of HSCs and KCs. It is known that the HSC-secreted Mac-2 binding protein glycan isomer (M2BPGi) has a function to activate Kupffer cells (KCs) in fibrotic liver. However, the importance and functional mechanism of liver regeneration by HSCs/M2BPGi/KCs axis in remnant liver after hepatectomy are still unknown. The aim of this study is to clarify whether the HSCs-derived M2BPGi can activate KCs in damaged-liver by not only fibrosis but also after hepatectomy and to elucidate the new molecular mechanism of liver regeneration by HSCs and KCs. Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs by proteomics approach. Further, the effect of Glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins on liver regeneration was examined in in vitro analysis and mouse hepatectomy model. Results: Although M2BPGi had no hepatocyte promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KCs-drived GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration in 70% hepatectomy mice and increased the survival rate in lethal 90% hepatectomy mice with liver failure. Conclusion: The M2BPGi activated-KCs extract the GRP78 which facilitates liver regeneration via activation of the proliferation potency of hepatocytes. Moreover, GRP78 administration could improve the survival in the lethal mice model. Our data suggested that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure in the clinic.

2021-06-29 | GSE179005 | GEO

Chronic TCDD treatment increases liver myofibroblast activation through aryl hydrocarbon receptor signaling in hepatocytes

Project description:The goal of this project was to determine how AhR activity in hepatocytes and HSCs impact liver fibrosis by studying mice with AhR-deficient hepatocytes (AhRΔHep) or AhR-deficient HSCs (AhRΔHSC) during TCDD-induced liver fibrosis as measured by evidence of steatosis, inflammation, HSC activation, and collagen deposition. Overall, our studies indicate that chronic TCDD exposure increases AhR signaling in hepatocytes that result in indirect HSC activation and the development of liver steatosis, whereas hepatic inflammation do not appear to play a major role.

2023-11-01 | GSE200710 | GEO

Characterization of hepatic stellate cells (HSC) genes in the normal liver or diverse liver fibrotic models by scRNAseq and bulk RNAseq.

Project description:Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality, develops almost exclusively in patients with chronic liver disease (CLD) and advanced fibrosis. Here we interrogated functions of hepatic stellate cells (HSC), the main source of liver fibroblasts, during hepatocarcinogenPesis. Genetic depletion, activation or inhibition established HSC as tumour-promoting in mouse models of HCC. HSC were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analysis of mouse and human HSC subpopulations and their associated mediators by single cell RNA-sequencing in conjunction with genetic ablation revealed dual functions of HSC in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSC (cyHSC), protected from hepatocyte death and HCC development. In contrast, type I collagen, enriched in activated myofibroblastic HSC (myHSC), promoted proliferation and tumour development via increased stiffness and TAZ activation in pretumoural hepatocytes and via activation of discoidin domain receptor 1 in established tumours. An increasing HSC dysbalance between cyHSC and myHSC during liver disease progression was associated with elevated HCC risk in patients. In summary, the dynamic shift of HSC subpopulations and their mediators during CLD is associated with a switch from HCC protection to HCC promotion.

2022-08-12 | GSE206409 | GEO

Opposing Roles of Hepatic Stellate Cell Subpopulations in Hepatocarcinogenesis

2022-08-26 | GSE212047 | GEO

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