The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of skeletal ("mesenchymal") stem cells (SSCs) found in BM stroma, have long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are both the self-renewing SSCs and the cells that transfer the HME at heterotopic sites upon transplantation.
Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.
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View SamplesWith the goal of specifically dissecting the toxicogenomic signatures of the helper-dependent (HD) human (HAd5) and canine (CAV-2) adenovirus, the VSV-G-pseudotyped SIN HIV-1 (LV) and the Adenoviral-associated vector 2/9 for human neurons (AAV2/9), we transduced a bona fide human neuronal system with HD-HAd5, HD-CAV-2, LV and AAV2/9, we analysed the transcriptional response of more than 47,000 transcripts using gene chips.
Differentiated neuroprogenitor cells incubated with human or canine adenovirus, or lentiviral vectors have distinct transcriptome profiles.
Specimen part
View SamplesBrain gene transfer using viral vectors will likely become a therapeutic option for several disorders. Helper-dependent (HD) canine adenovirus type 2 vectors (CAV-2) are well suited for this goal. Indeed, these vectors are poorly immunogenic, efficiently transduce neurons, are retrogradely transported to afferent structures in the brain, and lead to long-term transgene expression. CAV-2 vectors have been exploited to unravel behavior, cognition, neural networks, axonal transport and therapy for orphan diseases. Here we describe the HD-CAV-2 vector induced transcriptional response of human dopaminergic neurospheres derived from midbrain progenitors. In this 3D model system, brain cell functions and dynamics mimic several aspects the dynamic nature of human brain. With the goal of better understanding and characterizing HD CAV-2 for brain therapy, we analyzed the transcriptomic modulation induced by HD-CAV-2 in this brain model system.
Transcriptional Response of Human Neurospheres to Helper-Dependent CAV-2 Vectors Involves the Modulation of DNA Damage Response, Microtubule and Centromere Gene Groups.
Specimen part, Time
View SamplesHere we studied the effects of anticonvulsant drug exposure in a human embryonic stem cell (hESC) based neuro- developmental toxicity test (hESTn). During neural differentiation the cells were exposed, for either 1 or 7 days, to non-cytotoxic concentration ranges of valproic acid (VPA) or carbamazepine (CBZ), anti-epileptic drugs known to cause neurodevelopmental toxicity.
Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay.
Time
View SamplesAbout 10% of Down syndrome (DS) infants are born with a myeloproliferative disorder (DS-TMD) that spontaneously resolves within the first few months of life. About 20-30% of these infants subsequently develop acute megakaryoblastic leukemia (DS-AMKL). In order to understand differences that may exist between fetal and bone marrow megakaryocyte progenitor cell populations we flow sorted megakaryocyte progenitor cells and performed microarray expression analysis.
Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation.
Specimen part
View SamplesAbout 10% of Down syndrome (DS) infants are born with a myeloproliferative disorder (DS-TMD) that spontaneously resolves within the first few months of life. About 20-30% of these infants subsequently develop acute megakaryoblastic leukemia (DS-AMKL). In order to understand differences that may exist between fetal and bone marrow megakaryocyte progenitor cell populations we flow sorted megakaryocyte progenitor cells and performed microarray expression analysis.
Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation.
Specimen part
View SamplesEvaluation of the role of RIP4 in lung adenocarcinoma revealed that RIP4 inhibits STAT3 signaling in vitro and in vivo. Repression of RIP4 enhanced STAT3 signaling activation in KRAS LSL/G12D/wt; p53flox/flox murine tumors. This promoted cancer dedifferentiation through ECM remodeling
RIP4 inhibits STAT3 signaling to sustain lung adenocarcinoma differentiation.
Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens.
Specimen part, Cell line, Treatment, Time
View SamplesEpigenetic regulation is based upon a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets to treat a range of diseases including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach to control infection, persistence, and the resulting recurrent disease. The histone methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3 enriched chromatin domains. However, while EZH2/1 are implicated in repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and anti-pathogen pathways as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses.
Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens.
Cell line, Treatment, Time
View SamplesPsoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN- is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN--producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN- was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN- indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN- was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN- induced molecular and histological features characteristic of psoriasis lesions. IFN- increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN--treated skin. Thus, IFN-, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis.
A single intradermal injection of IFN-γ induces an inflammatory state in both non-lesional psoriatic and healthy skin.
Disease, Disease stage
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