Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson TX 75080, USA.
Southwest Transplant Alliance , Dallas, TX 75231, USA.
Sci Transl Med. 2022 Feb 16;14(632):eabj8186. doi: 10.1126/scitranslmed.abj8186.
Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha () expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.
伤害感受器是一种专门的感觉神经元,可检测到有害或潜在有害的刺激,存在于背根神经节(DRG)和三叉神经节中。这些神经元对于产生神经元信号至关重要,这些信号最终会产生疼痛的感觉。伤害感受器也是治疗急性和慢性疼痛的主要靶点。对小鼠伤害感受器的单细胞转录组学研究改变了我们对疼痛机制的理解。我们试图为人类伤害感受器生成等效信息,以确定伤害感受器的转录组特征,识别物种差异和潜在的药物靶点。我们使用空间转录组学对来自 8 位器官供体的单个 DRG 神经元的转录组进行了分子特征分析。我们鉴定出了 12 个人类感觉神经元簇,其中 5 个是 C 型伤害感受器,1 个 C 型低阈值机械感受器(LTMR),1 个 Aβ伤害感受器,2 个 Aδ,2 个 Aβ和 1 个本体感受器亚型。通过关注离子通道、G 蛋白偶联受体(GPCR)和其他药理学靶点的表达谱,我们为人类 DRG 中的潜在药物靶点提供了丰富的图谱,与小鼠感觉神经元转录组进行了直接比较。我们还将人类 DRG 神经元亚型与非人类灵长类动物进行了比较,发现许多细胞类型的基因表达模式具有保守性,但特定伤害感受器亚群存在分歧。最后,我们确定了人类 DRG 亚群转录组中的性别差异,包括在女性瘙痒受体富集的伤害感受器中,降钙素相关肽-α()的表达明显增加。这种对人类伤害感受器的全面空间特征描述可能为开发治疗急性和慢性疼痛疾病的更好方法开辟了道路。
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