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A human embryonic limb cell atlas resolved in space and time

Zhang, Bao and He, Peng and Lawrence, John E. and Wang, Shuaiyu and Tuck, Elizabeth and Williams, Brian and Roberts, Kenny and Kleshchevnikov, Vitalii and Mamanova, Lira and Bolt, Liam and Polanski, Krzysztof and Elmentaite, Rasa and Fasouli, Eirini S. and Prete, Martin and He, Xiaoling and Yayon, Nadav and Fu, Yixi and Yang, Hao and Liang, Chen and Zhang, Hui and FitzPatrick, David R. and Firth, Helen and Dean, Andrew and Barker, Roger A. and Storer, Mekayla A. and Wold, Barbara J. and Zhang, Hongbo and Teichmann, Sarah A. (2022) A human embryonic limb cell atlas resolved in space and time. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220511-693189600

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Abstract

Human limbs emerge during the fourth post-conception week as mesenchymal buds which develop into fully-formed limbs over the subsequent months. Limb development is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common. Decades of work with model organisms has outlined the fundamental processes underlying vertebrate limb development, but an in-depth characterisation of this process in humans has yet to be performed. Here we detail the development of the human embryonic limb across space and time, using both single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells, progressing from a restricted number of multipotent progenitors to myriad mature cell states, and identify several novel cell populations, including perineural fibroblasts and multiple distinct mesenchymal states. We uncover two waves of human muscle development, each characterised by different cell states regulated by separate gene expression programmes. We identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity and validate this by performing MSC knock down in human embryonic myoblasts, which results in significant upregulation of late myogenic genes. Spatially mapping the cell types of the limb across a range of gestational ages demonstrates a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncovers two transcriptionally and spatially distinct populations of the progress zone, which we term “outer” and “transitional” layers. The latter exhibits a transcriptomic profile similar to that of the chondrocyte lineage, but lacking the key chondrogenic transcription factors SOX5,6 & 9. Finally, we perform scRNA-seq on murine embryonic limbs to facilitate cross-species developmental comparison at single-cell resolution, finding substantial homology between the two species.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.04.27.489800DOIDiscussion Paper
ORCID:
AuthorORCID
He, Peng0000-0002-2457-3554
Roberts, Kenny0000-0001-6155-0821
Kleshchevnikov, Vitalii0000-0001-9110-7441
Wold, Barbara J.0000-0003-3235-8130
Teichmann, Sarah A.0000-0002-6294-6366
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. This version posted April 28, 2022. We thank Jana Lalakova for illustrating human limb syndromes. We thank Ken To for proofreading the manuscript. We thank Matt Thomson’s lab for help with mouse 10X loading. We thank members of the Teichmann lab, Zhang lab, Marioni lab, Haniffa lab and Behjati lab for discussion and feedback. This work was supported by the National Key Research and Development Program (grant 2019YFA0801703), National Natural Science Foundation of China (grant 31871370), Science and Technology Program of Guangzhou (grant 202002030429), and Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University (to H.Z.); China Postdoctoral Science Foundation (grant 2021M700936), and Natural Science Foundation of Guangdong (grant 2019A1515011342) (to S.W.). P.H holds a non-stipendiary research fellowship at St Edmund’s College, University of Cambridge. J.E.L is funded by the wellcome trust under the clinical PhD programme. Competing Interest Statement: In the past three years, S.A.T. has consulted for or been a member of scientific advisory boards at Roche, Qiagen, Genentech, Biogen, GlaxoSmithKline and ForeSite Labs. The remaining authors declare no competing interests.
Funders:
Funding AgencyGrant Number
National Key Research and Development Program of China2019YFA0801703
National Natural Science Foundation of China31871370
Science and Technology Program of Guangzhou202002030429
Sun Yat-sen UniversityUNSPECIFIED
China Postdoctoral Science Foundation2021M700936
Natural Science Foundation of Guangdong2019A1515011342
University of CambridgeUNSPECIFIED
Wellcome TrustUNSPECIFIED
DOI:10.1101/2022.04.27.489800
Record Number:CaltechAUTHORS:20220511-693189600
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220511-693189600
Official Citation:A human embryonic limb cell atlas resolved in space and time. Bao Zhang, Peng He, John E Lawrence, Shuaiyu Wang, Elizabeth Tuck, Brian Williams, Kenny Roberts, Vitalii Kleshchevnikov, Lira Mamanova, Liam Bolt, Krzysztof Polanski, Rasa Elmentaite, Eirini S Fasouli, Martin Prete, Xiaoling He, Nadav Yayon, Yixi Fu, Hao Yang, Chen Liang, Hui Zhang, David R. FitzPatrick, Helen Firth, Andrew Dean, Roger A Barker, Mekayla A Storer, Barbara J Wold, Hongbo Zhang, Sarah A Teichmann. bioRxiv 2022.04.27.489800; doi: https://doi.org/10.1101/2022.04.27.489800
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114671
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 May 2022 21:29
Last Modified:11 May 2022 21:29

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