Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain

Nociceptors are a type of sensory neuron that are 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 dorsal root ganglion (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 reveal that many key transcripts linked to pain are present. Markers 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 posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

Automated summary

Nociceptors are sensory neurons that play a crucial role in pain sensation. A recent study explored the potential of using sensory neurons derived from human induced pluripotent stem cells (hiPSCs) as a model for nociceptor research. The study compared the gene expression profiles of hiPSC-derived sensory neurons with mouse dorsal root ganglion (DRG) tissues and found similarities in key pain-related transcripts. Additionally, the study identified a translation factor called eIF5A as a potential target for inflammation-associated pain. Inhibition of eIF5A activity showed promising results in preventing pain hypersensitivity in vivo and reducing hiPSC activity in vitro.