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Molecular characterization of a precision-cut rat lung slice model for the evaluation of anti-fibrotic drugs

ABSTRACT: Molecular characterization of a precision-cut rat lung slice model for the evaluation of anti-fibrotic drugs

PROVIDER: PRJNA494086 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7945460_1.fastq.gz	Fastqsanger.gz
	SRR7945460_2.fastq.gz	Fastqsanger.gz
	SRR7945470_1.fastq.gz	Fastqsanger.gz
	SRR7945470_2.fastq.gz	Fastqsanger.gz
	SRR7945480_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Molecular characterization of a precision-cut rat lung slice model for the evaluation of anti-fibrotic drugs

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.

2018-10-02 | GSE120679 | GEO

Molecular Characterization of a Precision-Cut Rat Liver Slice Model for the Evaluation of Anti-Fibrotic Compounds

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

Molecular Characterization of a Precision-Cut Rat Liver Slice Model for the Evaluation of Anti-Fibrotic Compounds

Project description:Molecular Characterization of a Precision-Cut Rat Liver Slice Model for the Evaluation of Anti-Fibrotic Compounds

| PRJNA494582 | ENA

An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy

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.

2024-06-20 | GSE226702 | GEO

An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and for evaluating antiviral drugs

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, 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, which might reflect the heterogeneity of human populations. In particular, two cytokines (IL-8 and IP-10) are highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination reveals focal cytopathic effects late in the infection, which are largely limited to type II alveolar cells. 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 inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.

2023-03-01 | MSV000091383 | MassIVE

Transcriptome analysis of long rough dab (Hippoglossoides platessoides) liver slice culture exposed to benzo[a]pyrene.

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.

2024-09-09 | E-MTAB-13932 | biostudies-arrayexpress

RNA-seq of Atlantic salmon primary hepatocytes treated with alpha-linolenic acid

Project description:Primary hepatocytes were prepared from Atlantic salmon and grown for 8 days. Data from this experiment was compared to precision cut liver slice (PCLS) culture from Atlantic salmon.

2019-05-08 | E-MTAB-7368 | biostudies-arrayexpress

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

Project description:Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs

| PRJNA524343 | ENA

RNA-seq of precision cut liver slice (PCLS) culture before slicing and up to nine days after slicing

Project description:RNA-seq of precision cut liver slice (PCLS) culture before slicing and up to nine days after slicing

| PRJEB29531 | ENA

Annorade mRNA Sequencing Qualified the Transcriptome Analysis of Fresh and Warmed Tissue of Hepatocellular Carcinoma

Project description:Purpose: The aim of this study was to create a patient-derived slice model by combining cryopreservation technique with precision-cut slice culture method and explore its effectivity of predicting anti-cancer drug sensitivity in vitro. Methods: We prepared 0.3 mm thick tissue slices by a microtome and maintain its cell viability by cryopreservation technique. Slices were cultured individually in the presence or absence of regorafenib (REG) for 72 hours. Alterations in morphology and gene expression were assessed by histological and genetic analysis. Overall viability was also analyzed in tissue slices by CCK-8 quantification assay and fluorescent staining. Tissue morphology and cell viability could be evaluated to quantify drug effects. Results: Histological and genetic analysis showed that no significant alterations in morphology and gene expression were induced by vitrification‑based cryopreservation. The viability of warmed HCC tissues was up to 90% of the fresh tissues. The viability and proliferation could be retained for at least four days in filter culture system. The positive drug responses in precision-cut slice culture in vitro were evaluated by tissue morphology and cell viability. Conclusion: In summary, the successful application of precision-cut HCC slice culture combining cryopreservation technique in a systematic drug screen demonstrates the feasibility and utility of slice culture method for drug response.

2022-01-21 | GSE194095 | GEO

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