Opposing Roles of Hepatic Stellate Cell Subpopulations in Hepatocarcinogenesis
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ABSTRACT:
PROVIDER: PRJNA873690 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21201623_1.fastq.gz | Fastqsanger.gz | |||
| SRR21201623_2.fastq.gz | Fastqsanger.gz | |||
| SRR21201624_1.fastq.gz | Fastqsanger.gz | |||
| SRR21201624_2.fastq.gz | Fastqsanger.gz | |||
| SRR21201625_1.fastq.gz | Fastqsanger.gz |
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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. This SuperSeries is composed of the SubSeries listed below.
2022-08-26 | GSE212047 | GEO
Project description:Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts3, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion.
| S-EPMC9949942 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) 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 fibroblasts in the injured liver, during hepatocarcinogenesis. Genetic depletion, activation, or inhibition established HSC as tumour-promoting in different HCC models. HSC were enriched in the non-tumour environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Surprisingly, further analysis of mouse and human HSC subpopulations by single cell and single nucleus RNA-sequencing and their associated mediators 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 highly activated myofibroblastic HSC (myHSC), increased stiffness, TAZ activation, and subsequent hepatocyte proliferation, thereby promoting HCC development. An increasing HSC imbalance with decreased protective cyHSC and increased myHSC during liver disease progression was associated with elevated HCC risk in patients. In summary, our data suggest that the dynamic shift of HSC subpopulations during CLD and their mediators is associated with a switch from HCC protection to HCC promotion.
2022-05-01 | GSE174748 | GEO
Project description:Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.
| S-EPMC7419619 | biostudies-literature
Project description:Hepatic fibrosis is the strongest contributor to hepatocarcinogenesis in metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanisms have yet to be fully elucidated. In 94 human MASLD biopsy samples, artificial intelligence-based morphological phenotyping of hepatic fiber and multi-omics analyses revealed that insulin growth factor-binding protein 7 (IGFBP-7) secreted from senescent periportal endothelial cells might transform stellate cells into a hepatocarcinogenesis-promoting phenotype. To test the effect of IGFBP-7 on HSC, a hepatic stellate cell line, LX-2, was cultured with recombinant IGFBP-7 (100ng/mL), resulting in their transformation to a more activated form than the control.
2025-08-20 | GSE278593 | GEO
Project description:Subpopulations of activated hepatic stellate cells defined and inhibited by WT1 expression
| PRJNA400188 | ENA
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
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
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone.
2015-02-19 | GSE52253 | GEO
Project description:Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro-survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro-apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two-thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects.
| S-EPMC9277267 | biostudies-literature