英国威康桑格研究所Sarah A. Teichmann团队的最新研究，揭示了人类胚胎骨骼发育的多组学图谱。相关论文于2024年11月20日发表于国际学术期刊《自然》杂志。

据了解，人胚胎骨骼和关节的形成是由新生骨骼中祖细胞的协调分化决定。这些细胞的细胞状态、表观遗传特征和关键调控因子仍然未知。

研究人员对约336000个核液滴进行了成对转录组和表观遗传分析，并应用空间转录组学建立了孕后5到11周的，人胚胎关节和颅骨发育的多组学图谱。通过对转录和表观遗传学数据进行组合建模，研究揭示了整个胚胎骨骼中不同区域肢体和颅骨的生成轨迹，并进一步描述了支配膜内骨化和软骨内骨化的调控网络。

研究人员利用新工具ISS-Patcher对原位测序数据中的细胞群进行了空间定位，揭示了骨和关节形成过程中祖细胞的分区机制。通过轨迹分析，研究人员预测了来源于Schwann细胞的人类软骨细胞的潜在非典型细胞起源。

研究人员还开发了SNP2Cell，这是一种将细胞类型特异性调控网络，与骨关节炎等多基因性状联系起来的工具。利用该研究揭示的软骨轨迹，研究人员模拟了导致单基因颅骨发育不良的基因扰动，并揭示了潜在的细胞状态和发病机制。

这项工作揭示了骨骼和软骨成熟的详细动态调控图谱，推动了对人类骨骼发育过程中细胞命运决定的基本认识。

附：英文原文

Title: A multi-omic atlas of human embryonic skeletal development

Author: To, Ken, Fei, Lijiang, Pett, J. Patrick, Roberts, Kenny, Blain, Raphael, Polaski, Krzysztof, Li, Tong, Yayon, Nadav, He, Peng, Xu, Chuan, Cranley, James, Moy, Madelyn, Li, Ruoyan, Kanemaru, Kazumasa, Huang, Ni, Megas, Stathis, Richardson, Laura, Kapuge, Rakesh, Perera, Shani, Tuck, Elizabeth, Wilbrey-Clark, Anna, Mulas, Ilaria, Memi, Fani, Cakir, Batuhan, Predeus, Alexander V., Horsfall, David, Murray, Simon, Prete, Martin, Mazin, Pavel, He, Xiaoling, Meyer, Kerstin B., Haniffa, Muzlifah, Barker, Roger A., Bayraktar, Omer, Chdotal, Alain, Buckley, Christopher D., Teichmann, Sarah A.

Issue&Volume: 2024-11-20

Abstract: Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development.

DOI: 10.1038/s41586-024-08189-z

Source: https://www.nature.com/articles/s41586-024-08189-z