Tissue resident memory (Trm) represent a newly described memory T cell population. We have previously characterized a population of Trm that persists within the brain following acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm do not undergo recall expansion following dissociation from the tissue. Furthermore, these Trm do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells we compared the gene-expression profiles of Trm isolated from the brain to circulating memory T cells isolated from the spleen following an acute virus infection. Trm displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors and overexpressed several inhibitory receptors. Cumulatively, these data indicates that Trm are a distinct memory T cell population disconnected from the circulating memory T cell pool and displaying a unique molecular signature which likely results in optimal survival and function within their local environment.
The molecular signature of tissue resident memory CD8 T cells isolated from the brain.
Specimen part
View SamplesTranscription profiling by array of mouse male retinas to investigate IGF-I-induced chronic gliosis and retinal stress
Insulin-like growth factor I (IGF-I)-induced chronic gliosis and retinal stress lead to neurodegeneration in a mouse model of retinopathy.
Sex, Specimen part
View SamplesBackground: The terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human breast. We here demonstrate the impact on epithelium of two lineages of breast stromal fibroblasts, one of which accumulates in the TDLU while the other resides outside the TDLU in the interlobular stroma. Methods: The two lineages are prospectively isolated by FACS based on different expression levels of CD105 and CD26. The characteristics of the two fibroblast lineages are assessed by immunocytochemical staining and gene expression analysis. The differentiation capacity of the two fibroblast populations is determined by exposure to specific differentiating conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271low/MUC1high normal breast luminal epithelial cells are plated on fibroblast feeders for the observation of morphological development. Epithelial structure formation and polarization is shown by immunofluorescence and digitalized quantification of immunoperoxidase stained cultures. Results: Lobular fibroblasts are CD105high/CD26low while interlobular fibroblasts are CD105low/CD26high. Once isolated the two lineages remain phenotypically stable and functionally distinct in culture. Lobular fibroblasts have properties in common with bone marrow derived mesenchymal stem cells and they specifically convey growth and branching morphogenesis of epithelial progenitors. Conclusions: Two distinct functionally specialized fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial progenitors, i.e. the putative precursors of breast cancer.
Evidence of two distinct functionally specialized fibroblast lineages in breast stroma.
Specimen part
View SamplesEpithelial tumors can progress from a benign tissue overgrowth (hyperplasia) to a malignant neoplastic tumor, which is characterized by an increase in motility and invasiveness. The Cohen laboratory has developed an epithelial tumor model in which overexpression of the epidermal growth factor receptor gene (EGFR) leads to benign tissue hyperplasia. When combined with other cooperating factors, EGFR overexpression can lead to neoplasia and malignant metastasis.
Warburg Effect Metabolism Drives Neoplasia in a Drosophila Genetic Model of Epithelial Cancer.
Specimen part, Time
View SamplesWe have generated a large collection of normal human mammary epithelial cell strains from women aged 16 to 91 years, derived from primary tissues, to enable functional and molecular interrogation of aging. We demonstrate in finite-lifespan cultured and uncultured epithelial cells that aging is associated with reduction of myoepithelial cells and with increases in luminal cells expressing keratin 14 and integrin 6, traits that are expressed exclusively in myoepithelial cells in women under 30. We find that changes to the luminal lineage result from age-dependent expansion of multipotent progenitors that bear defects resulting in incompletely differentiated luminal cells. These findings were verified in vivo in normal breast tissues. Myoepithelial cells have been suggested to act as tumor suppressors, and progenitor cells are implicated as the etiological roots of mammary carcinomas. Thus with aging there is a shift in the balance of luminal/myoepithelial lineages, and changes in the functional spectrum of multipotent progenitors, which presages increased potential for malignant transformation.
Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.
Age, Specimen part
View SamplesDouble-stranded RNA-binding proteins are key elements in the intracellular localization of mRNA and its local translation. Staufen is a double-stranded RNA binding protein involved in the localised translation of specific mRNAs during Drosophila early development and neuronal cell fate. The human homologue Staufen1 forms RNA-containing complexes that include proteins involved in translation and motor proteins to allow their movement within the cell, but the mechanism underlying translation repression in these complexes is poorly understood. Here we show that human Staufen1-containing complexes contain essential elements of the gene silencing apparatus, like Ago1-3 proteins, and we describe a set of miRNAs specifically associated to complexes containing human Staufen1. Among these, miR124 stands out as particularly relevant because it appears enriched in human Staufen1 complexes and is over-expressed upon differentiation of human neuroblastoma cells in vitro. In agreement with these findings, we show that expression of human Staufen1 is essential for proper dendritic arborisation during neuroblastoma cell differentiation, yet it is not necessary for maintenance of the differentiated state, and suggest potential human Staufen1 mRNA targets involved in this process.
Human Staufen1 associates to miRNAs involved in neuronal cell differentiation and is required for correct dendritic formation.
Cell line
View SamplesThe transcriptional data from an integrative analysis of transcriptional and metabolic stress responses that provides a more complete understanding of the mechanisms by which genetic regulatory circuits mediate metabolic phenotype.
Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p.
No sample metadata fields
View SamplesTo ask whether MANF contributes to the rejuvenating effects of heterochronic parabiosis, we generated heterochronic pairs in which 20 month old WT mice were combined with either 4 month old MANFHet (O-YgHet) or WT (O-YgWT) littermates, and maintained for 5 weeks before analysis. Control pairs in which old WT mice were combined together (O-O) were used. Livers were collected from each animal in the pair and RNA was sequenced for 5 independent animals/condition. Overall design: RNA was extracted and sequenced for 5 animals/condition
MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.
Age, Subject
View SamplesIn the nervous system, neural stem cells (NSC) are necessary for the generation of new neurons and for cognitive function. Here we show that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, regulates the NSC pool. We find that adult FoxO3-/- mice have fewer NSC in vivo than wild type counterparts. NSC isolated from adult FoxO3-/- mice have decreased self-renewal and an impaired ability to generate different neural lineages. Identification of the FoxO3-dependent gene expression profile in NSC suggests that FoxO3 regulates the NSC pool by inducing a program of genes that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. The ability of FoxO3 to prevent the premature depletion of NSC might have important implications for counteracting brain aging in long-lived species.
FoxO3 regulates neural stem cell homeostasis.
Specimen part
View SamplesThe biotrophic fungus Ustilago maydis causes smut disease on maize (Zea mays L.), which is characterized by immense plant tumours. To establish disease and reprogram organ primordia to tumours, U. maydis deploys effector proteins in an organ-specific manner. However, the cellular contribution to leaf tumours remains unknown. We investigated leaf tumour formation on the tissue- and cell type-specific level. Cytology and metabolite analysis were deployed to understand the cellular basis for tumourigenesis. Laser-capture microdissection was performed to gain a cell-type specific transcriptome of U. maydis during tumour formation. In-vivo visualization of plant DNA synthesis identified bundle sheath cells as the origin of hyperplasic tumour cells, while mesophyll cells become hypertrophic tumour cells. Cell type specific transcriptome profiling of U. maydis revealed tailored expression of fungal effector genes. Moreover, U. maydis See1 was identified the first cell type specific fungal effector, being required for induction of cell cycle reactivation in bundle sheath cells. Identification of distinct cellular mechanisms in two different leave cell types, and See1 as an effector for induction of proliferation of bundle-sheath cells, are major steps in understanding U. maydis-induced tumor formation. Moreover, the cell-type specific U. maydis transcriptome data is a valuable resource to the scientific community. Overall design: To analyze the cell type specific transcriptome of U. maydis during the indcution of plant tumors, transcriptomic profiling of U. maydis from LCM-dissected tumour cells was done. At 4 dpi, SG200 infected HTT cells, bundle sheath-derived HPT cells, and SG200?see1 infected HTT cells (?see1 HTT) were isolated. As controls, mesophyll and bundle sheath cells from mock treated leaf tissue of the same age were isolated.
Cell type specific transcriptional reprogramming of maize leaves during Ustilago maydis induced tumor formation.
Specimen part, Subject
View Samples