Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205871 | GEO | 2023/09/20
REPOSITORIES: GEO
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Project description:Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that expression of Fibroblast growth factor 18 (Fgf18) is elevated in the livers of mice following induction of chronic liver fibrosis models. Deletion and overexpression of Fgf18 in hepatocytes attenuate and promote liver fibrosis, respectively. Single-cell RNA-sequencing revealed that Lrat+ quiescent hepatic stellate cells (HSCs) are increased in the livers of Fgf18 transgenic mice. Mechanistically, FGF18 stimulates the proliferation of quiescent HSCs by inducing the expression of Ccnd1, resulting in the development of liver fibrosis. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.
2023-09-26 | GSE188273 | GEO
Project description:Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.
2023-09-05 | GSE242032 | GEO
Project description:Purpose: To identify the alterations of genes transcriptional profile of livers obtained from Prmt1f/f mice and Lrat-Cre; Prmt1f/f mice treated with thioacetamide (TAA). Methods: Lrat-Cre mice were crossed with and Prmt1f/f mice to generate Lrat-Cre; Prmt1f/f mice. Prmt1f/f mice and Lrat-Cre; Prmt1f/f mice were treated with TAA (400mg/L, drinking water for 16 weeks) to induce liver fibrosis. Liver mRNA profiles of 10-week-old Prmt1f/f and Lrat-Cre; Prmt1f/f mice treated with TAA were generated by deep sequencing, using Illumina Novaseq 6000. We applied DESeq2 algorithm to filter the differentially expressed genes, after the significant analysis and FDR analysis under the following criteria: i) |log2FC| > 1 ; ii) Pvalue < 0.05. RT–PCR validation was performed using SYBR Green PCR Kit. Results: We identified 16916 transcripts in the livers of Prmt1f/f and Lrat-Cre; Prmt1f/f mice. 726 transcripts showed differential expression between Prmt1f/f and Lrat-Cre; Prmt1f/f livers, with a |log2FC| > 1 and P value < 0.05. Altered expression of 4 genes was confirmed by qRT–PCR. Conclusion: Our study represents the first detailed analysis of liver transcriptomes of Lrat-Cre; Prmt1f/f mice during liver fibrogenesis. RNA-seq based transcriptome analysis would provide us better understanding of complex biologic functions of Prmt1 in the hepatic stellate cell during the pricess of hepatic fibrogenesis in mice.
2022-02-07 | GSE196115 | GEO
Project description:Objective: To evaluate the composition and function of mural cell populations in human gingival tissues Results: Two mural cell clusters, RGS5+THY1+ and ACTA2+MYH11+ subpopulations, were identified and confirmed by histological staining and cross-validation with three different single-cell RNA sequencing datasets in the GEO database. RGS5+THY1+ cluster in perivascular areas possessed cellular protrusions and exhibited immunomodulatory and synthetic phenotypes. In contrast, the ACTA2+MYH11+ cluster strictly distributed around vessel walls was characterized by a contractile phenotype. Mural cells closely interacted with endothelial cells through PDGF and NOTCH3 signaling. Mural cell loss was detected in the v_i group and in hopeless periodontal teeth, which might be caused by tumor necrosis factor-alpha induced apoptosis.
2023-03-27 | GSE207502 | GEO
Project description:Purpose: To further explore FGF18's role in liver fibrosis beyond its known effects on HSC proliferation and TGFβ signaling, we performed RNA sequencing on primary HSCs treated with FGF18 or TGF-b. Methods: Fresh isolated HSCs were starved with DMEM containing 0.2% FBS for 24 hours and then left untreated or stimulated with FGF18 (100 ng/mL), TGFb1 (1 ng/mL). Total RNA was extracted from HSCs using RNeasy Micro Kit (74004, QIAGEN). RNA libraries were prepared using the SMART-Seq HT PLUS Kit (R400748, Takara Bio) according to the manufacturer's protocol.Paired-end sequencing (2 × 150 bp) was performed on a NovaSeq 6000 system (Illumina) to generate approximately 40M reads (20M pairs) per sample, with a target of 6G bases per sample. Results: RNA-seq analysis revealed that FGF18 induced Ccnd1 while suppressing profibrotic genes such as Col1a2, Col3a1, and Acta2, whereas TGFβ showed opposite effects. Among 62 genes upregulated by both factors, we focused on Spp1, encoding osteopontin, given its known role in tissue fibrosis.
2025-05-24 | GSE285364 | GEO
Project description:Purpose: Use scRNA Seq to find stromal subpopulations and define how these subpopulations contribute to salivary gland proacinar differentiation. Method: scRNA Seq on stromal enriched cells from E16 salivary organoids. Model closely related cells using PCA and UMAP regressions. Find genes that broadly and specifically define cell subpopulations. Results: The stromal fibroblasts have multiple subpopulations. Stromal cells can be subdivided by their expression of Pdgfra, Pdgfrb, Thy1, and Acta2. Conclusions: Organoids grown with FGF2 selects for Pdgfra expressing stroma and without FGF2 Acta2 stroma dominates.
2022-03-01 | GSE193041 | GEO
Project description:Background: Non-alcoholic fatty liver disease (NAFLD) affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. Approach and results: To identify liver-regulated pathways linking intra-hepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic APOF (encoding apolipoprotein F) expression showed the 4th strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic VLDL-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo, and reduced hepatocyte VLDL uptake by ~15% in vitro. Transcriptomic analysis of APOF-overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1, among others. Conclusion: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.
2022-06-29 | GSE203290 | GEO
Project description:We found that Retnla-Tg mice had significantly lower serum cholesterol levels than non-Tg mice on a high-fat diet (HFD). To explore the molecular mechanisms underlying the cholesterol-lowering effects of Retnla under hyperlipidemic conditions, we subjected age- and sex-matched Retnla-Tg and non-Tg mice to a HFD for 4 weeks. Using a microarray approach, we analyzed the hepatic gene expression profiles related to cholesterol metabolism, including catabolism, biosynthesis, and transport.
2014-06-06 | GSE58214 | GEO
Project description:We found that Retnla-Tg mice had significantly lower serum cholesterol levels than non-Tg mice on a high-fat diet (HFD). To explore the molecular mechanisms underlying the cholesterol-lowering effects of Retnla under hyperlipidemic conditions, we subjected age- and sex-matched Retnla-Tg and non-Tg mice to a HFD for 4 weeks. Using a microarray approach, we analyzed the hepatic gene expression profiles related to cholesterol metabolism, including catabolism, biosynthesis, and transport. Total RNA was extracted from livers of Retnla-Tg and non-Tg mice after feeding with a HFD for four weeks, and transcriptional profiling was performed on individual samples using Affymetrix Mouse Genome chips (MG 430 2.0 array).
2014-06-06 | E-GEOD-58214 | biostudies-arrayexpress
Project description:In human breast cancers, a phenotypically distinct minority population of tumorigenic cancer (TG) cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to studying human breast cancer. To do so, we utilized breast tumors of the MMTVWnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single cell suspensions, and FACS sorted on Thy1, CD24, and CD45. FACS sorted cells were then injected into recipient background FBV/NJ female mice. Thy1+CD24+ cancer cells, which constitute approximately 1-4% of tumor cells were highly enriched for cells capable of regenerating new tumors when compared to cells of the tumor that did not fit this profile (âNot Thy1+CD24+â). Resultant tumors were of the same phenotypic diversity as the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to âNot Thy1+CD24+â cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells. Experiment Overall Design: Expression profling were performed on 3 tumorigenic and 3 non tumorigenic samples of MMTV-Wnt-1 breast tumors. A gene signature was derived by comparing the gene expressions of 3 tumorigenic samples with 3 nontumorigenic samples
2008-06-16 | E-GEOD-8828 | biostudies-arrayexpress