Molecular Characterization of a Precision-Cut Rat Liver Slice Model for the Evaluation of Anti-Fibrotic Compounds
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ABSTRACT:
PROVIDER: PRJNA494582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7961940_1.fastq.gz | Fastqsanger.gz | |||
| SRR7961940_2.fastq.gz | Fastqsanger.gz | |||
| SRR7961950_1.fastq.gz | Fastqsanger.gz | |||
| SRR7961950_2.fastq.gz | Fastqsanger.gz | |||
| SRR7961960_1.fastq.gz | Fastqsanger.gz |
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Project description:Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the anti-fibrotic effect of experimental compounds in a physiologic environment. In this study using RNAquencing we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The Alk5 inhibitor SB525334, nintedanib and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, HA, IGFBP5 and WISP1, were further validated as efficacy endpoints for the evaluation of anti-fibrotic activity of experimental compounds. Finally, we showed that blockade of αV integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and to determine the efficacy of experimental compounds.
2018-10-04 | GSE120804 | GEO
Project description:The translation of novel pulmonary fibrosis therapies from preclinical models into the clinic represents a major challenge demonstrated by the high attrition rate of compounds that showed efficacy in preclinical models but demonstrated no significant beneficial effects in clinical trials. Precision-cut lung tissue slice (PCLS) contains all major cell types of the lung and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study pulmonary fibrosis. In this study, using RNA sequencing, we demonstrated that TGFβ1 induced robust fibrotic responses in the rat PCLS model as it changed the expression of genes functionally related to extracellular matrix remodeling, cell adhesion, epithelial-to-mesenchymal transition and various immune responses. Nintedanib, pirfenidone and sorafenib each reversed a subset of genes modulated by TGFβ1 and of those genes we identified 229 genes whose expression was reversed by all three drugs. These genes define a molecular signature characterizing many aspects of pulmonary fibrosis pathology and its attenuation in the rat PCLS fibrosis model. A panel of 12 genes and 3 secreted biomarkers including procollagen I, HA and WISP1 were validated as efficacy endpoints for the evaluation of anti-fibrotic activity of experimental compounds. Finally, we showed that blockade of αV integrins suppressed TGFβ1-induced fibrotic responses in the rat PCLS fibrosis model. Overall, our results suggest that the TGFβ1-induced rat PCLS fibrosis model may represent a valuable system for target validation and to determine the efficacy of experimental compounds.
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Project description:Molecular characterization of a precision-cut rat lung slice model for the evaluation of anti-fibrotic drugs
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Project description:Long rough dab (Hippoglossoides platessoides) is an important flatfish fish species in the north Atlantic arctic and sub-arctic marine foodweb that could be vulnerable to contaminant exposure from offshore petroleum related activities. The study was conducted to map transcriptome responses in long rough dab precision cut liver slice (PCLS) culture exposed to benzo[a]pyrene (BaP). BaP is a polyaromatic hydrocarbon (PAH) which is among the most toxic compounds found in crude oil. PCLS culture was performed under 10 µM BaP exposure for 72 h and transcriptome analysis (RNA-seq) analysis was performed to characterize de novo transcriptome of the liver and identify genes responding to BaP exposure.
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Project description:RNA-seq of precision cut liver slice (PCLS) culture before slicing and up to nine days after slicing
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Project description:Polar cod, a key fish species in the arctic marine foodweb is vulnerable to effects of pollution from offshore petroleum related activities in the Arctic and sub-arctic region. The study was conducted to map transcriptome responses to in Polar cod (Boreogadus saida) liver slice culture exposed to benzo[a]pyrene (BaP) in the presence or absence of physiological levels of ethynylestradiol (EE2). BaP is a polycyclic aromatic hydrocarbon (PAH), also found in crude oil contaminants. PAHs such as BaP are among the most toxic compounds of crude oil. Precision-cut liver slice cultures from five female polar cod (n = 5/ group, paired design) were exposed to BaP alone (10 µM), or in combination with low concentrations of EE2 (5 nM), to mimic physiological estradiol levels in early vitellogenic female fish. Transcriptome analysis (RNA-seq) was performed after 72 h exposure in culture. The results provide a global view of transcriptome responses to BaP, EE2 and their mixture. In the mixture exposure, BaP resulted attenuation of EE2 stimulated gene expression (anti-estrogenic effects). The results from this ex vivo experiment suggest that pollutants that activate the Ahr pathway such as the PAH compound BaP can result in anti-estrogenic effects that may lead to endocrine disruption in polar cod.
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Project description:RNA-seq of precision cut liver slice (PCLS) culture treated with increasing amounts of alpha-linolenic acid and insulin
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Project description:COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the deaths in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive and there is no existing model where the disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune response, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoherringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.
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Project description:This experiment was designed to test the effect of alpha-linolenic acid (ALA) and insulin on liver slices prepared from Atlantic salmon. Liver slices were incubated with increasing concentrations of ALA and insulin from 20µM to 100µM and 10nM to 100nM, respectively. RNA was subsequently sequenced and response was evaluated and compared to the expected response from Atlantic salmon feeding trials. The purpose of this was to evaluate liver slice culture as a cell culture system for studying lipid metabolism in Atlantic salmon.
2019-05-08 | E-MTAB-7366 | biostudies-arrayexpress
Project description:Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the antifibrotic effect of experimental compounds in a physiological environment. In this study using RNA sequencing, we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs, and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were further validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of ?V-integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and determining the efficacy of experimental compounds. NEW & NOTEWORTHY We investigated the antifibrotic activity of three compounds, the activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib, in a rat fibrotic precision-cut liver tissue slice model using RNA sequencing analysis. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were then established as efficacy end points to validate the antifibrotic activity of the ?V-integrin inhibitor CWHM12. This study demonstrated the value of the rat fibrotic PCLS model for the evaluation of antifibrotic drugs.
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