Neural stem cells were sorted according to their activated or quiescent state by flow cytometry using a set of 3 markers (LeX, CD24 and EGFR)
Distinct Molecular Signatures of Quiescent and Activated Adult Neural Stem Cells Reveal Specific Interactions with Their Microenvironment.
Sex, Specimen partView Samples
Microarrays were used to examine the genome-wide expression in FIH null, VHL null and VHL/FIH double null MEFs.
The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
Specimen partView Samples
tPTEN-/- mice display a deletion of the PTEN tumor suppressor gene specifically in T cells (cross PTEN flox/flox x lck-Cre). They develop T cell lymphoma with a primary thymic tumor and invasion of most organ at late stage of the disease.
Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas.
Specimen part, Disease, Disease stageView Samples
Natural killer (NK) cells are NKp46+CD3- lymphocytes that can perform granule-dependent cytotoxicity and produce interferon-gamma, when isolated from blood, lymphoid organs, lung, liver and uterus. Here we identify in dermis, gut lamina propria and cryptopatches, very distinct populations of NKp46+CD3- cells with reduced ability to degranulate and to produce interferon-gamma. In gut, the transcription factor RORgamma-t and CD127 (IL-7R alpha) defined a novel subset of NKp46+CD3- that is reminiscent of lymphoid tissue inducer (LTi)-like cells. Gut ROR gamma t+NKp46+ cells produced IL-22 in contrast to ROR-gamma t-independent lamina propria and dermis NK cells. These data show that LTi-like cells and NK cells share unanticipated similarities and reveal the heterogeneity of NKp46+CD3- cells in innate immunity, lymphoid organization and local tissue repair.
Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.
Sex, AgeView Samples
Pompe disease is caused by autosomal recessive mutations in the GAA gene, which encodes acid alpha-glucosidase. Although enzyme replacement therapy has recently improved patient survival greatly, the results in skeletal muscles and for advanced disease are still not satisfactory. Here, we report the derivation of Pompe disease induced pluripotent stem cells (PomD-iPSCs) and their potential for pathogenesis modeling, drug testing and disease marker identification. PomD-iPSCs maintained pluripotent features, and had low GAA activity and high glycogen content. Cardiomyocyte-like cells (CMLCs) differentiated from PomD-iPSCs recapitulated the hallmark Pompe disease pathophysiological phenotypes, including high levels of glycogen, abundant intracellular LAMP-1- or LC3-positive granules, and multiple ultrastructural aberrances. Drug rescue assessment showed that exposure of PomD-iPSC-derived CMLCs to rhGAA reversed the major pathologic phenotypes. Further, L-carnitine and 3- methyladenine treatment reduced defective cellular respiration and buildup of phagolysosomes, respectively, in the diseased cells. By comparative transcriptome analysis, we identified glycogen metabolism, lysosome and mitochondria related marker genes whose expression robustly correlated with the therapeutic effect of drug treatment in PomD-iPSC-derived CMLCs. Collectively, these results demonstrate that PomD-iPSCs are a promising in vitro disease model for development of novel therapeutic strategies for Pompe disease.
Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification.
Specimen partView Samples
T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLC1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLC1, however, PLC1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications.
Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.
Specimen part, TreatmentView Samples
Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer.
The transcription factor BACH2 promotes tumor immunosuppression.
Specimen partView Samples
We measured gene expression across the whole genome in a panel of lines selected for a wing shape trait (angular offset). The lines were created in separate experiments, originating from two widely separated populations, and including multiple replicates of one population, but all were created using the same selection regime and trait. Here we evaluate the data with two objectives: 1) to identify candidate wing shape genes for future testing and validation, and 2) to assess variation among lines in the outcome of identical selection regimes
Microarray analysis of replicate populations selected against a wing-shape correlation in Drosophila melanogaster.
No sample metadata fieldsView Samples
Mounting evidence points to a link between a cancer possessing stem-like properties and a worse prognosis. To understand the biology, a common approach is to integrate network biology with signal processing mechanics. That said, even with the right tools, predicting the risk for a highly susceptible target using only a handful of gene signatures remains very difficult. By compiling the expression profiles of a panel of tumor stem-like cells (TSLCs) originating in different tissues, comparing these to their parental tumor cells (PTCs) and the human embryonic stem cells (hESCs), and integrating network analysis with signaling mechanics, we propose that network topologically-weighted signaling processing measurements under tissue-specific conditions can provide scalable and predicable target identification.
Network biology of tumor stem-like cells identified a regulatory role of CBX5 in lung cancer.
Specimen partView Samples
Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently upregulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes.
The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence.
Cell line, TreatmentView Samples