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背根神经节的空间转录组学鉴定出人类伤害感受器的分子特征。

Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors.

机构信息

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.

出版信息

Sci Transl Med. 2022 Feb 16;14(632):eabj8186. doi: 10.1126/scitranslmed.abj8186.


DOI:10.1126/scitranslmed.abj8186
PMID:35171654
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9272153/
Abstract

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.

摘要

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。

相似文献

[1]
Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors.

Sci Transl Med. 2022-2-16

[2]
Nociceptor subtypes are born continuously over DRG development.

Dev Biol. 2021-11

[3]
Differences between Dorsal Root and Trigeminal Ganglion Nociceptors in Mice Revealed by Translational Profiling.

J Neurosci. 2019-6-28

[4]
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Pain. 2024-1-1

[5]
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J Pain. 2022-8

[6]
Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn.

J Comp Neurol. 2021-7-1

[7]
Neurochemical and Ultrastructural Characterization of Unmyelinated Non-peptidergic C-Nociceptors and C-Low Threshold Mechanoreceptors Projecting to Lamina II of the Mouse Spinal Cord.

Cell Mol Neurobiol. 2021-3

[8]
Cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function.

Nat Commun. 2023-1-23

[9]
Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia.

Sci Adv. 2024-6-21

[10]
HCN1 and HCN2 in Rat DRG neurons: levels in nociceptors and non-nociceptors, NT3-dependence and influence of CFA-induced skin inflammation on HCN2 and NT3 expression.

PLoS One. 2012-12-7

引用本文的文献

[1]
Identification of sensory fiber types in mouse temporomandibular joint tissues.

Sci Rep. 2025-9-1

[2]
Next-generation precision medicine for pain.

Mol Psychiatry. 2025-8-25

[3]
SLC45A4 is a pain gene encoding a neuronal polyamine transporter.

Nature. 2025-8-20

[4]
Ectopic Nociceptor Sprouting as a Key Peripheral Driver of Pain in Rheumatoid Arthritis.

Curr Rheumatol Rep. 2025-7-16

[5]
Spatial transcriptomic profiling of human paravertebral sympathetic chain ganglia reveals diabetes-induced neuroplasticity.

bioRxiv. 2025-6-25

[6]
sulfolipid-1 (Sl-1) increases the excitability of mouse and human TRPV1-positive sensory neurons in a YM254890-reversible fashion.

bioRxiv. 2025-6-29

[7]
Comparative transcriptome profiling of the lumbosacral dorsal root ganglia reveals sexually dimorphic gene expression in a murine model of coronavirus-induced neurodegeneration.

Am J Clin Exp Urol. 2025-6-15

[8]
Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models.

J Clin Invest. 2025-7-15

[9]
Gabapentin's effect on human dorsal root ganglia: Donor-specific electrophysiological and transcriptomic profiles.

Mol Pain. 2025

[10]
Etiological basis for chronic pain genetic variation in brain and dorsal root ganglia cell types.

medRxiv. 2025-7-5

本文引用的文献

[1]
Single-nucleus transcriptomic analysis of human dorsal root ganglion neurons.

Elife. 2021-11-26

[2]
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Brain. 2021-6-22

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Human cells and networks of pain: Transforming pain target identification and therapeutic development.

Neuron. 2021-5-5

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Annu Rev Neurosci. 2021-7-8

[5]
Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates.

Elife. 2021-4-23

[6]
Diversity of Receptor Expression in Central and Peripheral Mouse Neurons Estimated from Single Cell RNA Sequencing.

Neuroscience. 2021-5-21

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A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets.

Sci Signal. 2021-3-16

[8]
Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain.

Nat Commun. 2021-3-8

[9]
Considering sex as a biological variable will require a global shift in science culture.

Nat Neurosci. 2021-4

[10]
Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex.

Nat Neurosci. 2021-3

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