A multi-omic atlas of human embryonic skeletal development

• 成果类型: Article
• 署名作者: To, Ken; Fei, Lijiang; Pett, J. Patrick; Roberts, Kenny; Blain, Raphael; Polanski, 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 L.; 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.; Haniffe, Muzlifah; Barker, Roger A.; Bayraktar, Omer; Chedotal, Alain; Buckley, Christopher D.; Teichmanns, Sarah A.
• 署名单位: Wellcome Trust Sanger Institute; University of Cambridge; Institut National de la Sante et de la Recherche Medicale (Inserm); Centre National de la Recherche Scientifique (CNRS); Sorbonne Universite; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; University of California System; University of California San Francisco; University of Cambridge; University of Cambridge; University of Cambridge; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust; CHU Lyon; Universite Claude Bernard Lyon 1; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Oxford; Kennedy Institute for Rheumatology; Canadian Institute for Advanced Research (CIFAR)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5207
• DOI: 10.1038/s41586-024-08189-z
• 发表日期: 2024-11-21
• 页码: 657-+
• 关键词: growth; angiogenesis; promotes; joint; craniosynostosis; proliferation; osteogenesis; chondrocytes; cartilage; selection

摘要

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.