During gastrulation, epiblast cells are pluripotent and their fate is thought to be constrained principally by their position. Cell fate is progressively restricted by localised signalling cues from areas including the primitive streak (PS). However, it is unknown whether this restriction accompanies, at the single cell level, a reduction in potency. Investigation of these early transition events in vitro is possible via the use of Epiblast Stem Cells (EpiSCs), self-renewing pluripotent cell lines equivalent to the postimplantation epiblast. Strikingly, EpiSCs express various early lineage-specific markers in self-renewing conditions. However, it is unknown whether cells that express these markers are pluripotent, spontaneously differentiated, or biased towards specific lineages. Here we show that EpiSC are inherently heterogeneous and contain two major and mutually exclusive subpopulations with PS and neural characteristics respectively. Using differentiation assays and embryo grafting we demonstrate that PS-like EpiSCs are biased towards mesoderm and endoderm differentiation but they still retain their pluripotent character. The acquisition of a PS character by undifferentiated EpiSC is mediated by paracrine Wnt signalling. Elevation of Wnt activity promotes further restriction into PS-associated cell fates which occurs via the generation of distinct clonal mesendodermal and neuromesodermal precursors. Collectively, our data suggest that primed pluripotency encompasses a range of reversible lineage-biased states reflecting the birth of pioneer lineage precursors from a pool of uncommitted EpiSCs similar to the earliest cell fate restriction events taking place in the gastrula-stage epiblast.
Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors.
Sex, Specimen part
View SamplesThe study was performed to determine if there were alterations in the total RNA pool among the epidermal keratinocytes of K14 promotor-driven noggin overexpression compared with K14 promotor-driven BMP4 overexpression transgenic animals, which will directly relate to cellular chemistry and immune and sensory function. The total study is also aimed at determining alterations of transcrption factors and/or regulation of gene function, including methylation states and micro RNA control in keratinocytes following sensory challenge, particularly neuropathic and chronic pain conditions.
Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms.
Specimen part
View SamplesWe utilize gene expression and open chromatin footprinting data to build a gene regulatory network of key transcription factors that capture the cell and time-specific regulatory programs specified during human myeloid differentiation. Overall design: RNA-seq profiling of undifferentiated HL-60, differentiating macrophage, neutrophil, monocyte, and monocyte-derived macrophage cells.
Dynamic Gene Regulatory Networks of Human Myeloid Differentiation.
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View SamplesRATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with overtly scarred peripheral and basilar lung regions and macroscopically unaffected central lung areas. OBJECTIVES: To gain better insight into IPF pathobiology by comparing transcriptomic profiles of normal-appearing and scarred regions of IPF lung. METHODS: Lung tissue samples from macroscopically unaffected (normal-appearing, IPFn) and scarred (IPFs) regions of explanted IPF lungs were analyzed by RNASeq and compared with healthy control (HC) lung tissues. RT-qPCR and immunohistochemistry were used to confirm selected findings. MEASUREMENTS AND RESULTS: Numerous previously reported IPF-associated gene expression disturbances as well as additional differentially expressed mRNAs were observed. There were profound transcriptomic changes in IPFn compared with HC tissues, which included elevated expression of extracellular matrix-, immunity- and inflammation-related mRNAs. The magnitude and statistical significance of these changes were comparable or greater than those in the IPFs-to-HC comparison. When directly compared with IPFn, IPFs tissues demonstrated elevated expression of epithelial mucociliary mRNAs. Compared with HC, both IPFn and IPFs tissues demonstrated reduced expression of mRNAs related to solute carrier membrane transport and metabolic processes. Primary fibroblast cultures from IPFn and IPFs tissues were transcriptomically identical. CONCLUSIONS: Macroscopically normal-appearing IPF tissues demonstrate profound disease activity and substantially similar transcriptomic profiles to scarred areas. Differences between these tissues are due to cell types other than fibroblasts and notably include enhanced expression of mucociliary genes in scarred areas. Deranged epithelial homeostasis or possibly non-transcriptomic factors may thus explain the marked architectural differences between normal-appearing and terminally scarred lung in end-stage IPF. Overall design: RNASeq of 26 lung tissue samples from patients with IPF, including affected and unaffected areas of the lung, and from healthy controls
Transcriptomic evidence of immune activation in macroscopically normal-appearing and scarred lung tissues in idiopathic pulmonary fibrosis.
Specimen part, Disease, Subject
View Samplesassess the efficacy of dual PI3K/mTOR inhibitor with anti-lymphoma activity as single agent and in combination
PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.
Specimen part, Cell line, Treatment
View Samplesassess the gene expression profiling of 61 cell lines
PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.
Specimen part, Cell line
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