A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre
- Creators
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Molè, Matteo A.
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Coorens, Tim H. H.
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Shahbazi, Marta N.
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Weberling, Antonia
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Weatherbee, Bailey A. T.
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Gantner, Carlos W.
- Sancho-Serra, Carmen
- Richardson, Lucy
- Drinkwater, Abbie
- Syed, Najma
- Engley, Stephanie
- Snell, Philip
- Christie, Leila
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Elder, Kay
- Campbell, Alison
- Fishel, Simon
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Behjati, Sam
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Vento-Tormo, Roser
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Zernicka-Goetz, Magdalena
Abstract
Following implantation, the human embryo undergoes major morphogenetic transformations that establish the future body plan. While the molecular events underpinning this process are established in mice, they remain unknown in humans. Here we characterise key events of human embryo morphogenesis, in the period between implantation and gastrulation, using single-cell analyses and functional studies. First, the embryonic epiblast cells transition through different pluripotent states and act as a source of FGF signals that ensure proliferation of both embryonic and extra-embryonic tissues. In a subset of embryos, we identify a group of asymmetrically positioned extra-embryonic hypoblast cells expressing inhibitors of BMP, NODAL and WNT signalling pathways. We suggest that this group of cells can act as the anterior singalling centre to pattern the epiblast. These results provide insights into pluripotency state transitions, the role of FGF signalling and the specification of anterior-posterior axis during human embryo development.
Additional Information
© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 13 December 2020. Accepted 11 May 2021. Published 17 June 2021. We are grateful to all the patients donating their embryos, embryologists at the CARE, Bourn Hall and Herts & Essex clinics for help and support, and to colleagues in the M.Z.-G. laboratory. We thank Matthew Young for advice and help on data analysis and Krzysztof Polanski for helping with data sharing. We thank Connor Ross and the Jennifer Nichols group for the advice on using the LY inhibitor. We thank Martin Prete for creating the website. M.N.S. is funded by the European Molecular Biology Organisation (EMBO, Advanced EMBO fellowship) and UKRI Medical Research Council (MC_UP_1201/24). B.A.T.W. is funded by the Gates Cambridge Trust. Work in the laboratory of M.Z-G. is supported by grants from the Wellcome Trust (207415/Z/17/Z), Open Philanthropy/Silicon Valley, Curci and Weston Havens Foundations. S.B. is funded by the Wellcome Trust (Sanger core funding and personal fellowship to S.B.). Data availability. The raw sequencing and expression-count data with cell classifications have been deposited at the ArrayExpress database under accession code: E-MTAB-8060. Datasets can be visualised through the web portals www.humanembryo.org. Regarding previously published datasets used here, single-cell RNA-sequecning data from Xiang et al.23 and Zhou et al.24 are deposited in Gene Expression Omnibus (GEO) under accession numbers GSE136447 and GSE109555, respectively. In addition, cell line data from Takashima et al.43 are deposited at Array Express under accession number E-MTAB-2857. Cell line data from Theunissen et al.75 are deposited at GEO under accession number GSE59435. Cell line data from Rostovskaya et al.45 are deposited in GEO under accession number GSE 123055. Immunofluorescence data will be available from the corresponding authors upon reasonable request. Source data are provided with this paper. Code availability. Custom scripts used for analyses have been deposited at https://github.com/TimCoorens/EarlyEmbryo_scRNA (https://doi.org/10.5281/zenodo.4738657)77. This repository is linked to Zenodo and citable as Molè et al. A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre. To align reads, reference assembly GRCh38 was used [https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.26/]. Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Author Contributions. M.A.M., M.N.S. and A.W. designed, performed and analysed the experiments with the help of B.A.T.W. and C.G.; T.H.H.C. performed computational analyses of sequencing data, with supervision of R.V-T. and help from B.A.T.W.; R.V-T. and C.S-S. helped with the collection of the samples for scRNAseq. M.N.S. and A.W. prepared illustrations. A.C., S.F., L.R., A.D., N.S., S.E., K.E., L.C., P.S. oversaw and provided human embryos for these studies. S.B. and M.Z-G. conceived, supervised the project and provided funding. The manuscript was assembled with the help of all authors. The authors declare no competing interests. Additional information. Peer review information Nature Communications thanks Lilianna Solnica-Krezel, Patrick Tam and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.Attached Files
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Additional details
- Eprint ID
- 109495
- Resolver ID
- CaltechAUTHORS:20210618-210040654
- European Molecular Biology Organization (EMBO)
- MC_UP_1201/24
- Medical Research Council (UK)
- Gates Cambridge Trust
- 207415/Z/17/Z
- Wellcome Trust
- Open Philanthropy
- Shurl and Kay Curci Foundation
- Weston Havens Foundation
- Created
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2021-06-18Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering