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Single cell transcriptional profiling of cultured developing neurons upon inflammatory challenge [in vivo]

ABSTRACT: The communication between immune and central nervous system represents an emerging field in neuroscience with many potential consequences both in basic and translational medicine. Among the plethora of mechanisms which might be involved, it is now clear that that immune molecules released upon inflammatory state can modulate different physiological aspects of brain development, resulting in long-lasting pathological consequences which may interfere with normal behavior during adulthood. A common aspect of this immune molecule is to promote deep transcriptional changes responsible for long-term effects. Single-cell RNA sequencing is now becoming a cutting-edge technology for studying the genomic rearrangement occurring at single cell level in different experimental models, thus opening a new frontier in medicine. Here, by using primary cultured neurons as a simplified model for studying neuronal development, we study the long-term consequences of the proinflammatory cytokine interleukine-6 (IL-6) on developing neurons through a single-cell sequencing approach. Based on the immuneprofiling of the analyzed cells, we identified different neuronal and non-neuronal cell clusters whose transcriptional profile changed specifically upon the inflammatory stimulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE180344 | GEO | 2021/07/20

REPOSITORIES: GEO

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Single cell transcriptional profiling of cultured developing neurons upon inflammatory challenge [in vitro]

Project description:The communication between immune and central nervous system represents an emerging field in neuroscience with many potential consequences both in basic and translational medicine. Among the plethora of mechanisms which might be involved, it is now clear that that immune molecules released upon inflammatory state can modulate different physiological aspects of brain development, resulting in long-lasting pathological consequences which may interfere with normal behavior during adulthood. A common aspect of this immune molecule is to promote deep transcriptional changes responsible for long-term effects. Single-cell RNA sequencing is now becoming a cutting-edge technology for studying the genomic rearrangement occurring at single cell level in different experimental models, thus opening a new frontier in medicine. Here, by using primary cultured neurons as a simplified model for studying neuronal development, we study the long-term consequences of the proinflammatory cytokine interleukine-6 (IL-6) on developing neurons through a single-cell sequencing approach. Based on the immuneprofiling of the analyzed cells, we identified different neuronal and non-neuronal cell clusters whose transcriptional profile changed specifically upon the inflammatory stimulation.

2021-05-13 | GSE130803 | GEO

Genome sequencing coupled with iPSC technology identifies GTDC1 as a novel candidate gene involved in Neurodevelopmental Disorders

Project description:We identified genomic structural alterations of six patients with signs of neurodevelopmental disorder (NDDs) that harbour chromosomal rearrangements using large-insert paired-end tag sequencing (DNA-PET). This technique allowed the refinement of chromosomal breakpoints and lead to the identification of seven disrupted genes (GNAQ, RBFOX3, UNC5D, TMEM47, NCAPG2, GTDC1 and XIAP). For one patient we filtered the entire panel of structural variations (SVs) with his parents and identified a unique SV that disrupted a single gene: GTDC1. We then validated the functional consequences of the chromosomal breakpoint disruption of GTDC1 by using patient-derived iPSCs. By differentiating these cells into neural progenitor cells (NPCs) and neurons, we interrogated the disease process at the cellular level and observed defects in the proliferation and glycosylation status of NPCs and also defects in neuronal maturation and function. We compared these results with GTDC1-deficient wild-type human NPCs and neurons, and observed similar phenotypic features as in the patient-derived cells which confirm that GTDC1 is involved in the patient’s phenotype. We show here that the combination of genomic screening with iPSCs technology provides a mechanistic insight into possible contributory effects of candidate genes implicated in NDDs and for personalized medicine. Structural variations were identified by long insert DNA paired-end tag (DNA-PET) sequencing, a mate-pair sequencing approach.

2014-09-03 | E-GEOD-51430 | biostudies-arrayexpress

A single therapeutic early-in-life antibiotic course alters host immunologic development

Project description:Broad-spectrum antibiotics are frequently prescribed to children. The period of early-childhood represents a time where the developing microbiota may be more sensitive to environmental perturbations, which thus might have long-lasting host consequences. We hypothesized that even a single early-life broad-spectrum antibiotic course at a therapeutic dose (PAT) leads to durable alterations in both the gut microbiota and host immunity. In C57BL/6 mice, a single early-life tylosin (macrolide) course markedly altered the intestinal microbiome, and affected specific intestinal T-cell populations and secretory IgA expression, but PAT-exposed adult dams had minimal immunologic alterations. No immunological effects were detected in PAT-exposed germ-free animals; indicating that microbiota are required for the observed activities. Together these results indicate the impact of a single therapeutic early-life antibiotic course altering the microbiota and modulating host immune phenotypes that persist long after exposure has ceased.

2017-09-19 | E-MTAB-5101 | biostudies-arrayexpress

Long term culture of genome-stable bipotent progenitor cells from adult human liver

2015-01-15 | GSE63859 | GEO

Long term culture of genome-stable bipotent progenitor cells from adult human liver

Project description:Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bi-potent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from Î±1-antitrypsin deficiency and Alagille Syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine and gene therapy. We generated arrays from whole human liver tissue, and human liver derived cultures maintained in our defined medium. Genes 4 fold differentially expressed were used for the clustering analsyis (see matrix 1). For the genes enriched in organoid cultures grown in ERFHNic+A compared to ERFHnic we normalized the arrays by substracting the liver tissue 1 array to the culture arrays. Then we calculated the fold difference between the ERFHNic+A and the ERFHNic samples (see matrix 2).

2015-01-15 | E-GEOD-63859 | biostudies-arrayexpress

Transcriptome Analysis of Human Induced Excitatory Neurons Supports a Strong Effect of Clozapine on Cholesterol Biosynthesis

Project description:Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought to be the mechanism underlying their therapeutic effects. Nevertheless, other less studied consequences of antipsychotics on neuronal function may contribute to their efficacy. Revealing the complete picture behind their action is of paramount importance for precision medicine and accurate drug selection. Progress in cell engineering allows the generation of induced pluripotent stem cells (iPSCs) and their differentiation to a variety of neuronal types, providing new tools to study antipsychotics. Here we use excitatory cortical neurons derived from iPSCs to explore their response to therapeutic levels of Clozapine as measured by their transcriptomic output, a proxy for neuronal homeostasis. To our surprise, but in agreement with the results of many investigators studying glial-like cells, Clozapine had a very strong effect on cholesterol metabolism. More than a quarter (12) of all annotated cholesterol genes (46) in the genome were significantly changed at FDR<0.1, all upregulated. This is a 35-fold enrichment with an adjusted p = 8 x10-11. Notably no other functional category showed evidence of enrichment. Cholesterol is a major component of the neuronal membrane and myelin but it does not cross the blood brain barrier, it is produced locally mostly by glia but also by neurons. By singling out increased expression of cholesterol metabolism genes as the main response of cortical excitatory neurons to antipsychotics, our work supports the hypothesis that cholesterol metabolism may be a contributing mechanism to the beneficial effects of Clozapine and possibly other antipsychotics.

2021-02-11 | GSE163161 | GEO

The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti- tumor immunity

Project description:Given that TREX1-deficient tumor cells showed a growth delay in immunocompetent but not immunodeficient hosts, we characterize the consequences of CT26 tumor-intrinsic TREX1 loss on the host immune system by performing single-cell RNA sequencing on intra-tumoral immune cells sorted from control and TREX1 KO CT26 tumors.

2024-03-12 | E-MTAB-13823 | biostudies-arrayexpress

Enteric Nervous System Derived IL-18 Orchestrates Mucosal Barrier Immunity [DropSeq]

Project description:Using DropSeq single cell RNA sequencing, we report that neuronal derived-IL-18 is required for goblet cell expression of intestinal antimicrobial protein expression Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the anti-microbial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA-hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron derived IL-18 signaling controls tissue wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.

2019-12-12 | GSE141809 | GEO

Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells [ChIP-seq]

Project description:Direct conversion of somatic cells into neurons holds great promise for regenerative medicine. However, neuronal conversion is relatively inefficient in human cells compared to mouse cells. It has been unclear what might be the key barriers to reprogramming in human cells. We recently elucidated an RNA program mediated by the polypyrimidine tract binding protein PTB to convert mouse embryonic fibroblasts (MEFs) into functional neurons. In human adult fibroblasts (HAFs), however, we unexpectedly found that invoking the documented PTB–REST–miR-124 loop generates only immature neurons. We now report that the functionality requires sequential inactivation of PTB and the PTB paralog nPTB in HAFs. Inactivation of nPTB triggers another self-enforcing loop essential for neuronal maturation, which comprises nPTB, the transcription factor BRN2, and miR-9. These findings suggest that two separate gatekeepers control neuronal conversion and maturation and consecutively overcoming these gatekeepers enables deterministic reprogramming of HAFs into functional neurons.

2016-04-25 | GSE74814 | GEO

Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells [RNA-seq]

2016-04-25 | GSE77523 | GEO

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