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NOCICEPTRA: Gene and microRNA signatures and their trajectories characterizing human iPSC-derived nociceptor maturation

ABSTRACT: Nociceptors are specialized sensory neurons implicated in the reception and transduction of painful stimuli. Many pain disorders directly affect nociceptors but mechanistic insight into underlying pathway regulations is limited by the translational paresis from animal models to human pain disorders. Although transcriptomic data are available for rodent and post-mortem patient samples, no comprehensive transcriptomic data are currently available for human nociceptor development. Here, we performed paired long and small RNA sequencing for six timepoints during nociceptor differentiation from three different human iPSC cell lines. Complex bioinformatics analyses for differential gene expression, protein-protein interactions and mRNA targeting by microRNAs revealed five distinct differentiation stages with critical hub genes and microRNAs guiding nociceptor development. The online resource platform NOCICEPTRA was specifically developed to visualize respective mRNA and microRNA trajectories, as well as query disease specific pathways, thereby enabling researchers to determine susceptibility windows for nociceptor-associated disorders as well as possible new treatment targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161530 | GEO | 2021/09/06

REPOSITORIES: GEO

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Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

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Expression data from FACS purified nociceptor neurons from peripheral sensory ganglia

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Cytokines reprogram airway sensory neurons in asthma

Project description:Nociceptor neurons play a crucial role in maintaining the body’s homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons’ activity.

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