Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of COPD patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and NK cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative data sets, gene sets defined by poly I:C-induced DEGs were enriched in the molecular profiles of chronic obstructive pulmonary disease (COPD), but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients.
Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD.
Sex, Specimen part, Time
View SamplesGenomic profiling of bleomycin- and saline-treated mice across 7 timepoints (1, 2, 7, 14, 21, 28, 35 days post treatment) was carried out in C57BL6/J mice to determine the phases of response to bleomycin treatment which correspond to onset of active pulmonary fibrosis.
Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.
Sex, Specimen part, Treatment, Time
View SamplesRorb is essential for rod photoreceptor development in the mouse retina. Using Affymetrix mouse GeneChips, we have generated expression profiles of the +/+, Rorb-/- , +/+;CrxpNrl and Rorb-/-;CrxpNrl retina at P14 and P28.
Retinoid-related orphan nuclear receptor RORbeta is an early-acting factor in rod photoreceptor development.
Specimen part
View SamplesThe regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle, or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/-Catenin signaling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated -Catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and -Catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs prior to their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involve unanticipated functions of -Catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.
A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate.
Specimen part
View SamplesThe Melanoma-associated Antigen gene family (MAGE) generally encodes for tumour antigens. We recently have identified one of the MAGE gene members, Mageb16 to be highly expressed in undifferentiated murine embryonic stem cells (mESCs). The role of Mageb16 for the differentiation of the pluripotent stem cells is completely unknown. Here we demonstrate that Mageb16 (41 kDa) is distributed in cytosol and/or in surface membrane in undifferentiated mESCs. A transcriptome study was performed with differentiated short hairpin RNA (shRNA)-mediated Mageb16 knockdown (KD ESCs) and scrambled control (SCR) ESCs until a period of 22 days. Mageb16 KD ESCs mainly differentiated towards mesodermal derivatives such as cardiovascular lineages. Mesoderm-oriented differentiation initiated biological processes such as adipogenesis, osteogenesis, limb morphogenesis and spermatogenesis were significantly enriched in the differentiated Mageb16 KD ESCs. Cardiomyogenesis in differentiated KD mESCs was stronger when compared to differentiated SCR and wild mESCs. The expression of non-coding RNA (ncRNA) Lin28a and other epigenetic regulatory genes, nucleocytoplasmic trafficking and genes participating in spermatogenesis have also declined faster in the differentiating Mageb16 KD ESCs. We conclude that Mageb16 plays a crucial role for differentiation of ESCs, specifically to the mesodermal lineages. Regulative epigenetic networks and nucleocytoplasmic modifications induced by Mageb16 may play a role for the critical role of Mageb16 for the ESCs differentiation.
Depletion of Mageb16 induces differentiation of pluripotent stem cells predominantly into mesodermal derivatives.
Sex, Specimen part
View SamplesGene expression profiling of newborn lung tissue revealed few changes in compound FGFR3/FGFR4 deficient mice, consistent with their normal lung morphology at birth, suggesting the sequence of events leading to the phenotype initiates after birth in this model.
Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis.
Age, Specimen part
View SamplesOur previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity.
The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2.
Specimen part, Disease
View SamplesSalivary glands are essential structures that secrete saliva to the oral cavity and maintain oral health. Development of salivary glands in mice and humans is controlled by mesenchymally expressed fibroblast growth factor-10 (FGF10). Using single cell RNA-seq atlas of the salivary gland and a tamoxifen inducible Fgf10CreERT2:R26-tdTomato mouse we show that FGF10pos cells are exclusively mesenchymal until postnatal day 5 (P5), but after P7, there is a switch in expression and only epithelial FGF10pos cells are observed after P15. Further RNAseq analysis of sorted mesenchymal and epithelial FGF10pos cells shows that the epithelial FGF10pos populations express the hallmark of ancient ionocyte signature Foxi1, Foxi2, Ascl3 and the cystic fibrosis transmembrane conductance regulator (Cftr). We propose that epithelial FGF10pos cells are specialized salivary gland ionocytes that are important for the ionic modification of saliva. In addition, they maintain FGF10-dependent glands homeostasis via communication with FGFR2b-expressing epithelial progenitor and myoepithelial cells Overall design: Comparison of Fgf10+ expressing cell mRNA profiles from submandibular glands of 7 day old pups and 60 days old mice in duplicate
A mesenchymal to epithelial switch in Fgf10 expression specifies an evolutionary-conserved population of ionocytes in salivary glands.
Specimen part, Genotype, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation.
Specimen part, Cell line
View SamplesIkaros family DNA binding proteins are critical regulators of B cell development. To identify Ikaros-regulated genes in pre-B cells we performed gene expression studies at enhanced temporal resolution.
Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation.
Specimen part, Cell line
View Samples