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GSE82111
Mus musculus
10 Downloadable Samples
Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets. Immortalized cell lines recapitulate NR biology very poorly and primary cultures are laborious and require a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology since technical uncertainty early in drug development is the cause of many preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective tissues stem cells, can serve as a novel (preclinical) model system to study NR biology and targeteability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. NR mRNA expression patterns were similar to the respective tissues, indicating their suitability for NR research. Metabolic NRs Fxr, Lxr, Lxr, Ppar, and Ppar were responsive to ligands in an NR-dependent fashion, as demonstrated by regulation of expression and binding to endogenous target genes. Transcriptome analyses of wildtype colonic organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the known function of PPARs and Rosiglitazone in vivo. In conclusion, our results demonstrate that organoids constitutes a versatile and promising in vitro system to study NR biology and targeteability.
Publication Title
Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 mol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown to depend on the presence of the gut microbiota, because hyperproliferation was completely eliminated by antibiotics, although heme-induced luminal cytotoxicity was sustained in these mice. Colon mucosa transcriptomics revealed that antibiotics block heme-induced differential expression of oncogenes, tumor suppressors, and cell turnover genes, implying that antibiotic treatment prevented the heme-dependent cytotoxic micelles to reach the epithelium. Our results indicate that this occurs because antibiotics reinforce the mucus barrier by eliminating sulfide-producing bacteria and mucin-degrading bacteria (e.g., Akkermansia). Sulfide potently reduces disulfide bonds and can drive mucin denaturation and microbial access to the mucus layer. This reduction results in formation of trisulfides that can be detected in vitro and in vivo. Therefore, trisulfides can serve as a novel marker of colonic mucolysis and thus as a proxy for mucus barrier reduction. In feces, antibiotics drastically decreased trisulfides but increased mucin polymers that can be lysed by sulfide. We conclude that the gut microbiota is required for heme-induced epithelial hyperproliferation and hyperplasia because of the capacity to reduce mucus barrier function.
Publication Title
Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
Illumina HiSeq 2000
Description
To provide further insight about the effects of prolonged Ezh2 inhibition in glioblastoma using preclinical mouse models and doxycycline-inducible shRNAs that mimic the effects of a selective EZH2 inhibitor. We demonstrate that prolonged Ezh2-depletion causes a robust switch in cell fate, including significantly enhanced proliferation and DNA damage repair and activation of part of the pluripotency network, resulting in altered tumor cell identity and tumor progression. Overall design: SVZ derived neural stem cells (NSCs) were isolated from 7 days old p53;Ink4a/Arf;Krasv12;LucR compound conditional mice and cultured in NSC specific serum-free medium supplemented with 20ng/ml of both EGF and bFGF (R&D systems). NSCs were grown adhesion-free for the first passages to eliminate non-sphere-forming cells. Next, cells were grown adherent on poly-L-Ornithine and Laminin plates and three times infected with lentiviral CMV-Cre. These floxed, tumorigenic cells are further referred as glioma initiating cells (GICs). Next, GICs were infected with a tet-inducible, doxycycline-responsive short hairpin construct (FH1-tUTG-shEzh2). After FACS sorting for GFP, GICs were injected intracranial in NOD-SCID mice and treated with or without doxycycline in the drinking water
Publication Title
Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 30 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st), Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject, Time
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st), Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA.
Publication Title
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.1 ST Array (hugene11st)
Description
Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA.
Publication Title
Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject, Time
View Samples- Homo sapiens
- 16 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
We recently reported the scalable in vitro production of functional stem cell-derived cells. Here we extend this approach to generate SC- cells from Type 1 diabetic patients (T1D), a cell type that is destroyed during disease progression and has not been possible to extensively study. These cells express cell markers, respond to glucose both in vitro and in vivo, prevent alloxan-induced diabetes in mice, and respond to anti-diabetic drugs. Furthermore, we use an in vitro disease model to demonstrate the cells respond to different forms of cell stress. Using these assays, we find no major differences in T1D SC- cells compared to SC- cells derived from non-diabetic patients (ND). These results show that T1D SC- cells can be used for the treatment of diabetes, drug screening, and the study of cell biology.
Publication Title
Generation of stem cell-derived β-cells from patients with type 1 diabetes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bi-directionally towards pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of chief cells. By lineage tracing using a Troy-eGFP-ires-CreERT2 allele, single marked cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy+ chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific, 'plastic' subset of differentiated chief cells capable of replenishing entire gastric units, essentially serving as a quiescent reserve stem cell.
Publication Title
Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 76 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Background
Publication Title
Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression.
Sample Metadata Fields
Specimen part
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
The goal of this RNA-Seq analysis was to identify genes differentially expressed in a C. elegans strain overexpressing HSP-90 in the neurons compared to control (N2) animals. C. elegans overexpressing HSP-90 protein in the neurons activate transcellular chaperone signalling that enhances organismal proteostasis. This study aimed to identify components of the signalling pathway responsible for this effect. Overall design: Gene expression profile of L4 C. elegans wild type (N2) animals compared to L4 C. elegans overexpressing HSP-90::GFP in the neurons, using a neuron-specific promoter (F25B3.3p), grown at 20C. 3 replicates of each sample.
Publication Title
A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.
Sample Metadata Fields
Cell line, Subject
View Samples