Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain.
Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain.
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人类感觉神经元mRNA表达的整体分析揭示eIF5A是炎性疼痛的保守靶点。
DOI：
10.1096/fj.202101933rr
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发表时间：
2022-07
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伤害感受器是一种感觉神经元，与大多数形式的疼痛是不可或缺的。伤害感受器敏化的靶向破坏提供了预防疼痛的独特机会。一种新兴的伤害感受器模型是源自人类干细胞的感觉神经元。在这里，我们对五组进行了高通量测序：分化前的人诱导多能干细胞（hiPSC）、成熟的hiPSC衍生的感觉神经元、含有hiPSC衍生的星形胶质细胞和感觉神经元的成熟共培养物、小鼠背根神经节（DRG）组织和小鼠DRG培养物。伤害感受器和星形胶质细胞的共培养促进DRG组织中富集的转录物的表达。hiPSC模型与组织样品的比较揭示，存在许多与疼痛相关的关键转录物。在成熟hiPSC中检测到指示DRG中存在的一系列神经元亚型的标志物。有趣的是，翻译因子在物种和培养系统中保持一致的高表达水平。作为该资源效用的概念证明，我们验证了真核起始因子5A（eIF5A）在DRG组织和hiPSC样品中的表达。eIF5A受到其活性所需的独特的翻译后羟腐胺赖氨酸修饰。抑制羟腐胺赖氨酸的生物合成防止了体内炎症介质引起的痛觉过敏，并降低了体外hiPSC活性。总的来说，我们的结果阐明了hiPSC感觉神经元模型的转录组。我们通过对eIF5A的研究为这种资源提供了一个示范。我们的研究结果揭示了羟腐胺赖氨酸作为男性炎症相关疼痛的潜在靶点。
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 post-translational 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.