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GSE54387
Mus musculus
4 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Little is known about the function of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) generated from diabetics, as this could potentially limit subsequent therapeutic use in this patient population.
Publication Title
Pravastatin reverses obesity-induced dysfunction of induced pluripotent stem cell-derived endothelial cells via a nitric oxide-dependent mechanism.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
IlluminaHiSeq2000
Description
We investigated the ALDH2*2 genetic polymorphism and its underlying mechanisms for the first time in a human model system of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation confers elevated levels of reactive oxygen species (ROS) and toxic aldehydes such as 4HNE, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. ALDH2 exerts control of cell survival decisions via modulation of oxidative stress levels. This regulatory circuitry was found to be dysfunctional in the loss-of-function ALDH2*2 genotype, causing upregulation of apoptosis in cardiomyocytes following ischemic insult. These results reveal a novel function of the metabolic enzyme ALDH2 in modulation of cell survival decisions. Overall design: Molecular mechanism of increased ischemic damage in cardiomyocytes of ALDH2*2 genotype.
Publication Title
Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 38 Downloadable Samples
Description
We profiled the transcriptome of cardiomyocytes from hiPSCs throughout differentiation and at a single cell level to identify subpopulations. We further studied on the transcription factors NR2F2, TBX5, and HEY2 in these subpopulations. Overall design: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we performed bulk RNA-seq on hiPSCs undergoing differentiation into cardiomyocytes over an extended time course followed by single-cell RNA-seq at a later time point (day 30). These analyses identified novel single-cell populations, characterized by the distinct or overlapping expression of TBX5, NR2F2, HEY2, ISL1, JARID2, and HOPX transcription factors. Analysis of RNA-seq data from hiPSC-CMs both during differentiation in vitro and from human heart tissues suggests these transcription factors underlie physiologically distinct lineages. Using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, CYTOF, and single-cell Western analysis, we now demonstrate that these transcription factors play an essential role in specification of early atrial (NR2F2) and late ventricular (HEY2) cardiomyocytes. We RNA-sequenced NR2F2, TBX5, HEY2 gene edited lines as well as day 30 hiPSC-CMs overexpressing NR2F2, TBX5, and HEY2. These new targets, sequencing data, and methods provide a platform for improved investigation of in vitro cardiac heterogeneity.
Publication Title
Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
ABSTRACT Background: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. Methods and Results: Human iPSC-CMs were infected with a luciferase-expressing mutant of the coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs. Viral proliferation on hiPSC-CMs was subsequently quantified using bioluminescence imaging. For drug screening, select antiviral compounds including interferon beta 1 (IFN1), ribavirin, pyrrolidine dithiocarbamate (PDTC), and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of some of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with the reported drug effects in previous studies. Finally, mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways within these hiPSC-CMs after IFN1 treatment. Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to confirm antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that could be used to screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion.
Publication Title
Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Tyrosine kinase inhibitors (TKIs), despite efficacy as anti-cancer therapies, are associated with cardiovascular side effects ranging from induced arrhythmias to heart failure. We have utilized patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), generated from 11 healthy individuals and 2 patients receiving cancer treatment, to screen FDA-approved TKIs for cardiotoxicities by measuring alterations in cardiomyocyte viability, contractility, electrophysiology, calcium handling, and signaling. With these data, we generated a cardiac safety index to assess cardiotoxicities of existing TKIs. Many TKIs with a low cardiac safety index exhibit cardiotoxicity in patients. We also derived endothelial cells (hiPSC-ECs) and cardiac fibroblasts (hiPSC-CFs) to examine cell type-specific cardiotoxicities. Using high-throughput screening, we determined that VEGFR2/PDGFR-inhibiting TKIs caused cardiotoxicity in hiPSC-CMs, hiPSC-ECs, and hiPSC-CFs. Using phosphoprotein analysis, we determined that VEGFR2/PDGFR-inhibiting TKIs led to a compensatory increase in cardioprotective insulin and insulin-like growth factor (IGF) signaling in hiPSC-CMs. Activating cardioprotective signaling with exogenous insulin or IGF1 improved hiPSC-CM viability during co-treatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs. Thus, hiPSC-CMs can be used to screen for cardiovascular toxicities associated with anti-cancer TKIs, correlating with clinical phenotypes. This approach provides unexpected insights, as illustrated by our finding that toxicity can be alleviated via cardioprotective insulin/IGF signaling.
Publication Title
High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells.
Sample Metadata Fields
Treatment, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
The gene expression of bone marrow Hdc-/- and WT (LSK, Lin-c-kit+Sca-1+) hematopoetic stem and progenitor cells were isolated from Hdc-/- or WT mice. Cells were sorted by the cell surface markers of LSK total RNA was isolated from sorted 2,000 HSPCs using the ARCTURUS PicoPure RNA isolation kit (Life Technologies). cDNA was amplified and libraries were constructed by using the SMARTer Ultra Low Input RNA kit (Clontech Laboratories) and the Nextera XT DNA Library Preparation kit (Illumina) according to the respective manufacturer's instructions. Sequencing was performed on the Illumina HiSeq2500 platform. Overall design: a. Hdc-/- bone marrow HSPC (n=4) b. WT bone marrow HSPC (n=4)
Publication Title
Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3<sup>+</sup> regulatory T cells in murine colon cancer.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Bone marrow Hdc-GFP+/hi and Hdc-GFP-/loCD11b+Gr1+ cells were isolated from bones from histidine decarboxylase (Hdc) green fluorescent protein (Hdc-GFP) mice Hdc-GFP+/hiCD11b+Gr1+ cells and Hdc-GFP-/loCD11b+Gr1+ cells were sorted by combinations of GFP and myeloid cell surface markers CD11b and Gr1 and their differential mRNA expression compared with Affymetrix microarrays.
Publication Title
Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3<sup>+</sup> regulatory T cells in murine colon cancer.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
BACKGROUND: The transcript levels of many genes exhibit significant variation in tissue samples from inbred laboratory mice. A microarray experiment was designed to separate transcript abundance variation across samples from adipose, heart, kidney, and liver tissues of C57BL/6J mice into within-mouse and between-mouse components. Within-mouse variance captures variation due to heterogeneity of gene expression within tissues, RNA-extraction, and array processing. Between-mouse variance reflects differences in transcript levels between these genetically identical mice. Many biological sources can contribute to heterogeneous transcript levels within a tissue sample including inherent stochasticity of biochemical processes such as intrinsic and extrinsic noise within cells and differences in cell-type composition which can result from heterogeneity of stem and progenitor cell populations. Differences in global signaling patterns between individuals and micro-environmental influences such as interactions with pathogens and cage mates can also contribute to variation, but are likely to contribute more to the between-mouse variance component.
Publication Title
Stochastic variation of transcript abundance in C57BL/6J mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Rattus norvegicus
- 47 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Although a number of animal model studies have addressed changes in gene expression in the parenchyma and their relationship to emphysema, much less is known about the pathogenesis of cigarette smoke-induced small airway remodeling. In this study, we exposed rat tracheal explants to whole smoke for 15 minutes, and then cultured the explants in air. The airway transcriptome was evaluated using RAE 230_2 GeneChips. By 2 hours after starting smoke exposure, expression levels of 502 genes were changed up or down by more than 1.5 times (p values <0.01 or less), and by 24 hours, 1870 genes were significantly changed up or down. These included genes involved in anti-oxidant protection, epithelial defense and remodeling, inflammatory mediators and transcription factors, and a number of unexpected genes including the MMP-12 inducer, tachykinin-1 (substance P). Pre-treatment of the explants with 1 x 10-7 M dexamethasone reduced the number of significantly changed genes by approximately 47% at 2 hr and 68% at 24 hours, and in almost all instances, reduced the magnitude of the smoke-induced changes. We conclude that even a very brief exposure to cigarette smoke can lead to rapid changes in the expression of a large number of genes in rat tracheal explants, and that these effects are directly mediated by smoke, without a need for exogenous inflammatory cells. Steroids, contrary to the usual belief, are able to ameliorate many of these changes, at least in this very acute model.
Publication Title
Modification of the rat airway explant transcriptome by cigarette smoke.
Sample Metadata Fields
Specimen part, Treatment
View Samples