A human embryonic limb cell atlas resolved in space and time

Bao Zhang, Peng He, John E. G. Lawrence, Shuaiyu Wang, Elizabeth Tuck, Brian A. Williams, Kenny Roberts, Vitalii Kleshchevnikov, Lira Mamanova, Liam Bolt, Krzysztof Polanski, Tong Li, Rasa Elmentaite, Eirini S. Fasouli, Martin Prete, Xiaoling He, Nadav Yayon, Yixi Fu, Hao Yang, Chen Liang, Hui Zhang, Raphael Blain, Alain Chedotal, David R. FitzPatrick, Helen Firth, Andrew Dean, Omer Ali Bayraktar, John C. Marioni, Roger A. Barker, Mekayla A. Storer, Barbara J. Wold, Hongbo Zhang () and Sarah A. Teichmann ()
Additional contact information
Bao Zhang: Sun Yat-sen University
Peng He: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus
John E. G. Lawrence: Wellcome Sanger Institute, Wellcome Genome Campus
Shuaiyu Wang: Sun Yat-sen University
Elizabeth Tuck: Wellcome Sanger Institute, Wellcome Genome Campus
Brian A. Williams: Division of Biology and Biological Engineering, California Institute of Technology
Kenny Roberts: Wellcome Sanger Institute, Wellcome Genome Campus
Vitalii Kleshchevnikov: Wellcome Sanger Institute, Wellcome Genome Campus
Lira Mamanova: Wellcome Sanger Institute, Wellcome Genome Campus
Liam Bolt: Wellcome Sanger Institute, Wellcome Genome Campus
Krzysztof Polanski: Wellcome Sanger Institute, Wellcome Genome Campus
Tong Li: Wellcome Sanger Institute, Wellcome Genome Campus
Rasa Elmentaite: Wellcome Sanger Institute, Wellcome Genome Campus
Eirini S. Fasouli: Wellcome Sanger Institute, Wellcome Genome Campus
Martin Prete: Wellcome Sanger Institute, Wellcome Genome Campus
Xiaoling He: University of Cambridge
Nadav Yayon: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus
Yixi Fu: Sun Yat-sen University
Hao Yang: Sun Yat-sen University
Chen Liang: Sun Yat-sen University
Hui Zhang: Sun Yat-sen University
Raphael Blain: Sorbonne Université, INSERM, CNRS, Institut de la Vision
Alain Chedotal: Sorbonne Université, INSERM, CNRS, Institut de la Vision
David R. FitzPatrick: University of Edinburgh, WGH
Helen Firth: Wellcome Sanger Institute, Wellcome Genome Campus
Andrew Dean: Cambridge University Hospitals NHS Foundation
Omer Ali Bayraktar: Wellcome Sanger Institute, Wellcome Genome Campus
John C. Marioni: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus
Roger A. Barker: University of Cambridge
Mekayla A. Storer: University of Cambridge
Barbara J. Wold: Division of Biology and Biological Engineering, California Institute of Technology
Hongbo Zhang: Sun Yat-sen University
Sarah A. Teichmann: Wellcome Sanger Institute, Wellcome Genome Campus

Nature, 2024, vol. 635, issue 8039, 668-678

Abstract: Abstract Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.

Date: 2024
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DOI: 10.1038/s41586-023-06806-x

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