Modelling pain states with hiPSC derived sensory neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA777452 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16761018_1.fastq.gz | Fastqsanger.gz | |||
| SRR16761018_2.fastq.gz | Fastqsanger.gz | |||
| SRR16761019_1.fastq.gz | Fastqsanger.gz | |||
| SRR16761019_2.fastq.gz | Fastqsanger.gz | |||
| SRR16761020_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the development of a sensory neuron differentiation protocol which can be used to produce populations of nociceptive sensory neurons. Following transcriptomic and electrophysiological characterisation, we used cultures to investigate molecular pain pathways by exposing cells to three pain related stimuli: heat, cold and a migraine model. Samples were taken at four time points, up to 18 hours after stimulus exposure. Bulk RNA sequencing of samples showed that for temperature models, gene expression changes were dominated by those involved in cell stress and cell death mechanisms. For the migraine model, we obseved a complex pattern of exposure-associated gene expression changes, including the up-regulation of several genes and pathways involved in neuronal and synaptic function.
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Project description:Nociceptors are a type of sensory neurons that is integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse DRG tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveals that many key genes linked to pain are present. Marker genes indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique post-translational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo. One of two hypusine inhibitors diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a proof of concept for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.
2022-06-24 | GSE192566 | GEO
Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
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Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
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Project description:The dorsal root ganglion (DRG) neurons take in charge of primary detection and transmission of peripheral pain and itch stimuli, however, as two distinct noxious sensation, it is still attractive for this field that how the DRG neurons differentially response and code pain and itch. Here, we investigate the response and activation spectrum of DRG neurons under peripheral pain and itch stimuli using in vivo two-photon calcium imaging, and find differences in the responsive intensity to pain and itch between multisensory neurons (both pain and itch) and single-sensory neurons (either pain or itch). Besides, single-cell RNA sequencing (scRNA-seq) is used to reveal the heterogeneity of distinct subpopulations based on their expression of pain- or itch-related marker genes and indicates the similarity and difference of their transcriptomic changes under chronic pain and itch. Our results will provide fundamental insights to the peripheral pain and itch differential coding mechanism, moreover, benefit the development of pain and itch therapies.
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Project description:Molecular characterization of the individual neuron types existing in the primate dorsal root ganglion and the relation to model organisms used for studying somatosensation and pain is critical for understanding the cellular origin of chronic pain and for translational aspects of biomedical research. However, molecular insights into the primate dorsal root ganglion are missing and a systematic comparison of strategies for somatosensation between the mouse and primates is lacking. Here we classify non-human primate sensory neurons based on their transcriptome and identify neuronal types with heritability to chronic pain. We identify nine neuronal types and use machine learning to expose an overall cross-species conserved strategy and shared taxonomy for nociception, although with differences at individual gene level, highlighting the importance of incorporating primate knowledge for the successful translation of discoveries in rodent model organisms. Genomic loci implicated in chronic pain were mapped onto specific primate sensory neuron types to identify the cellular origin of chronic pain. The common-variant genome-wide association results for chronic pain point to the same cells at the same pain sites and concentrate on two different neuronal types between pain disorders, suggesting that causative cell types and molecular mechanisms are different between different pain conditions.
2021-03-11 | GSE148238 | GEO
Project description:The nervous system has a tremendous capacity for experience-dependent plasticity. In response to changes in activity induced by environmental cues, many types of neurons undergo a process known as homeostatic plasticity, which serves to maintain overall network function in the face of mounting experience-dependent changes in synaptic strengths. Homeostatic plasticity involves both changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in both animal models and in human patients. However, it is not known whether homeostatic plasticity is engaged in sensory neurons under normal conditions or whether dysfunction in these homeostatic mechanisms might contribute to the pathophysiology of chronic pain. To address these questions, we tested the impact of sustained depolarization on various measures of excitability in mouse and human sensory neurons. Depolarization induced by 30mM KCl induces a compensatory decrease in the excitability of both mouse and human sensory neurons. Moreover, we also find that voltage-gated sodium currents are robustly inhibited in mouse sensory neurons after chronic depolarization, thus contributing to the overall decrease in neuronal excitability and serving as a potential regulatory mechanism to drive intrinsic neuronal homeostatic control. Our results indicate that mouse and human sensory neurons undergo homeostatic regulation of intrinsic excitability in response to sustained depolarization. Decreased efficacy of these homeostatic mechanisms could potentially contribute to the development of pathological conditions, including chronic pain.
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Project description:Chronic pain is a significant public health issue that is often refractory to existing therapies. Here we combine ChIP-seq and ATAC-seq to identify cis-regulatory elements that show differential chromatin accessibility, and revealed transcription factor (TF) binding motifs with functionally regulation in the dorsal root ganglion (DRG) after nerve injury. We integrated RNA-seq to understand how differential chromatin accessibility after nerve injury may influence gene expression. We performed motif analysis of the differentially accessible H3K4me1 enriched regions to identify enrichment of TF motifs. Using TF protein arrays and ChIP-qPCR, we confirmed C/EBPg binding to a differentially accessible sequence and use RNA-seq to identify processes in which C/EBPg plays an important role. Our findings offer insights into those TF motifs that are associated with chronic pain. These data show how interactions between chromatin landscapes and TF expression patterns work together to determine gene expression programs in primary sensory neurons after nerve injury.
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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].
2011-07-14 | E-GEOD-30691 | biostudies-arrayexpress
Project description:The overall aim of the experiment is to understand the phenotype of mature mouse olfactory sensory neurons by analyzing the transcripts expressed and enriched in them as compared to the rest of the cell types in the olfactory epithelium (consisting of immature neurons, supporting cells, progenitor cells and cells in lamina propria) and brain ( with out the olfactory bulbs). Comparision with the other cell types in the olfactory epithelium should eliminate the transcripts commonly expressed in the olfactory epithelium and comparision with brain will eliminate the transcripts common to most neurons. Our gene chip data indicates that mature mouse olfactory sensory neurons express 10,000 genes. Mature OSNs specifically contained three clusters of over represented Gene ontology categories: smell, ion transport and cilia. Analysis for the functionally over represented categories among the transcripts with a positive signal in the mature OSNs yielded largely broad categories common to all cells with the exception of chromatin modelling and RNA processing categories. Biological process categories of movement, development and immune response came as under represented categories. Experiment Overall Design: To purify mature olfactory neurons we took advantage of the OMP-GFP mice. OMP(olfactory marker protein) is expressed specifically in mature olfactory and vomeronasal sensory neurons. In the OMP-GFP mice the coding region of OMP is replaced by GFP. We purified OSNs from the rest of the epithelium from these mice by using FACS. . We used the Affymetrix gene chips mouse expression set 430 (consisting of 430A and 430B chips). Our gene chip data is extensively validated by insitu hybridizations.
2008-06-13 | E-GEOD-4915 | biostudies-arrayexpress