Decoding transcriptional identity in developing human sensory neurons and organoid modeling

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2024-11-12 DOI:10.1016/j.cell.2024.10.023

Tian Lu, Mengdi Wang, Wei Zhou, Qi Ni, Yuanlei Yue, Wei Wang, Yingchao Shi, Zeyuan Liu, Changlin Li, Bei Hong, Xin Zhou, Suijuan Zhong, Kaikai Wang, Bo Zeng, Jun Zhang, Wei Wang, Xu Zhang, Qian Wu, Xiaoqun Wang

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Abstract

Dorsal root ganglia (DRGs) play a crucial role in processing sensory information, making it essential to understand their development. Here, we construct a single-cell spatiotemporal transcriptomic atlas of human embryonic DRG. This atlas reveals the diversity of cell types and highlights the extrinsic signaling cascades and intrinsic regulatory hierarchies that guide cell fate decisions, including neuronal/glial lineage restriction, sensory neuron differentiation and specification, and the formation of neuron-satellite glial cell (SGC) units. Additionally, we identify a human-enriched NTRK3⁺/DCC⁺ nociceptor subtype, which is involved in multimodal nociceptive processing. Mimicking the programmed activation of signaling pathways in vivo, we successfully establish functional human DRG organoids and underscore the critical roles of transcriptional regulators in the fate commitment of unspecialized sensory neurons (uSNs). Overall, our research elucidates the multilevel signaling pathways and transcription factor (TF) regulatory hierarchies that underpin the diversity of somatosensory neurons, emphasizing the phenotypic distinctions in human nociceptor subtypes.

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解码发育中人类感觉神经元的转录特征和类器官模型

背根神经节（DRG）在处理感觉信息方面起着至关重要的作用，因此了解其发育过程至关重要。在这里，我们构建了人类胚胎背根神经节的单细胞时空转录组图谱。该图谱揭示了细胞类型的多样性，并突出了指导细胞命运决定的外在信号级联和内在调控层次，包括神经元/神经胶质细胞系的限制、感觉神经元的分化和规格化以及神经元-卫星胶质细胞（SGC）单元的形成。此外，我们还发现了一种人类丰富的 NTRK3+/DCC+ 痛觉感受器亚型，它参与了多模式痛觉处理。模仿体内信号通路的程序化激活，我们成功地建立了功能性人DRG器官组织，并强调了转录调节因子在非特化感觉神经元（uSNs）命运承诺中的关键作用。总之，我们的研究阐明了支撑躯体感觉神经元多样性的多级信号通路和转录因子（TF）调控层次，强调了人类痛觉感受器亚型的表型差异。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.