Introduction of brain tumor-relevant genetic aberrations initiates different subtypes of brain tumor-like neoplasms in cerebral organoids Overall design: Comparison of abundances (TPM) from different brain tumor organoid groups
Author Correction: Genetically engineered cerebral organoids model brain tumor formation.
Specimen part, Subject
View SamplesIntroduction of brain tumor-relevant genetic aberrations initiates different subtypes of brain tumor-like neoplasms in cerebral organoids Overall design: Comparison of transcriptomes from different brain tumor organoid groups
Author Correction: Genetically engineered cerebral organoids model brain tumor formation.
Specimen part, Subject
View SamplesIn order to identify the effects of TFEB overexpression on the hela cells transcriptome, we performed Affymetrix Gene-Chip hybridization experiments for the hela TFEB stable clones
TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy.
Cell line
View SamplesThe nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist.
Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo.
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View SamplesDiabetes is prevalent worldwide and associated with severe health complications, including blood vessel damage that leads to cardiovascular disease and death. Here we report the development of a 3D blood vessel organoid culture system from human pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into interconnected capillary networks enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused human vascular tree, including human arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the basal membrane, a hallmark of human diabetic microangiopathy. Human blood vessel, exposed in vivo to a diabetic milieu in mice, also mimick the microvascular changes in diabetic patients. We finally performed a drug screen and uncovered ?-secretase and DLL4-Notch3 as key drivers of “diabetic” vasculopathy in human blood vessels in vitro and in vivo. Thus, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable to model and identify drug targets for diabetic vasculopathy, which affects hundreds of millions of patients. Overall design: Vascular organoids were differentiated from iPSC cells and cultured in control, diabetic or diabetic media supplemented with the gamma-secretase inhibitor DAPT. Endothelial cells (CD31 positive) and pericytes (PDGFRbeta positive) were isolated by FACS and subjected to RNA Seq. Accordingly, CD31 positive endothelial cells and PDGFRbeta positive pericytes differentiated from iPS cells in 2D as a well as primary endothelial (HUVECS) and pericytes (Placenta) were FACS sorted and subjected to RNA Seq.
Human blood vessel organoids as a model of diabetic vasculopathy.
Sex, Specimen part, Cell line, Subject
View SamplesDiabetes is prevalent worldwide and associated with severe health complications, including blood vessel damage that leads to cardiovascular disease and death. We report the development of 3D blood vessel organoids from human embryonic and induced pluripotent stem cells. These human blood vessel organoids contain endothelium, perivascular pericytes, and basal membranes, and self-assemble into lumenized interconnected capillary networks. We treat these vascular organoids with hyperglycemia and inflammatory cytokines in vitro, which leads to basement membrane thickening, a structural hallmark of diabetic patient. To compare differential gene expression we performed RNAseq on endothelial cells, derived from control (NG) or diabetic (DI) vascular organoids. Overall design: Vascular organoids were differentiated from human iPS cells and treated for 3 weeks with a diabetic media containing 75mM Glucose, 1ng/mL TNF-a, 1ng/mL IL6 (DI) or left untreated in 17mM Glucose (NG). Endothelial cells were FACS sorted for CD31 directly into Trizol and stored at -80°C before RNA preparation. The 2 NG and 2 DI are pools of sorted endothelial cells from multiple vascular organoids (>100) from 2 independent differentiations/treatments.
Human blood vessel organoids as a model of diabetic vasculopathy.
Sex, Specimen part, Cell line, Subject
View SamplesThis study explores the underlying pathogenic mechanisms of congenital intrinsic obstruction of the ureteropelvic junction. A hedgehog-dependent mechanism underlying mammalin intrinsic ureteropelvic obstruction is defined. Overall design: Tissue was microdissected from the kidney-ureter junction at E13.5, one day after the onset of Ptc2-lacZ expression, from PTC-/-MM mice; 2 PTC2+ and 2 PTC2- cell populations were isolated using antibodies specific for PTC2 and FACS sorting.
Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.
Specimen part, Cell line, Subject
View SamplesRNA-seq and expression profile of WT and ZFP57 KO ES cells Overall design: RNA was extracted from both cell lines, PolyA RNA were extracted and RNA-seq was performed
In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Direct genesis of functional rodent and human schwann cells from skin mesenchymal precursors.
Specimen part
View SamplesRecent reports of directed reprogramming have raised questions about the stability of cell lineages. Here, we have addressed this issue, focusing upon skin-derived precursors (SKPs), a dermally-derived precursor cell. We show by lineage tracing that murine SKPs from dorsal skin originate from mesenchymal and not neural crest-derived cells. These mesenchymally-derived SKPs can, without genetic manipulation, generate functional Schwann cells, a neural crest cell type, and are highly similar at the transcriptional level to Schwann cells isolated from the peripheral nerve. This is not a mouse-specific phenomenon, since human SKPs that are highly similar at the transcriptome level can be made from facial (neural crest-derived) and foreskin (mesodermally-derived) dermis, and the mesodermally-derived SKPs can make myelinating Schwann cells. Thus, non-neural crest-derived mesenchymal precursors can differentiate into bona fide peripheral glia in the absence of genetic manipulation, suggesting that developmentally-defined lineage boundaries are more flexible than widely thought.
Direct genesis of functional rodent and human schwann cells from skin mesenchymal precursors.
Specimen part
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