Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids

Gastruloids are three-dimensional aggregates of embryonic stem cells that display key features of mammalian development after implantation, including germ-layer specification and axial organization1-3. To date, the expression pattern of only a small number of genes in gastruloids has been explored w...

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Autores: van den Brink, Susanne C., Alemany, Anna, van Batenburg, Vincent, Moris, Naomi, Blotenburg, Marloes, Vivié, Judith, Baillie-Johnson, Peter, Nichols, Jennifer, Sonnen, Katharina F., Martinez Arias, Alfonso, van Oudenaarden, Alexander
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2020
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/56609
Acceso en línea:http://hdl.handle.net/10230/56609
http://dx.doi.org/10.1038/s41586-020-2024-3
Access Level:acceso abierto
Palabra clave:Embryology
Embryonic stem cells
Mesoderm
RNA sequencing
Synthetic organisms
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network_name_str España
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dc.title.none.fl_str_mv Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
title Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
spellingShingle Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
van den Brink, Susanne C.
Embryology
Embryonic stem cells
Mesoderm
RNA sequencing
Synthetic organisms
title_short Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
title_full Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
title_fullStr Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
title_full_unstemmed Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
title_sort Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
dc.creator.none.fl_str_mv van den Brink, Susanne C.
Alemany, Anna
van Batenburg, Vincent
Moris, Naomi
Blotenburg, Marloes
Vivié, Judith
Baillie-Johnson, Peter
Nichols, Jennifer
Sonnen, Katharina F.
Martinez Arias, Alfonso
van Oudenaarden, Alexander
author van den Brink, Susanne C.
author_facet van den Brink, Susanne C.
Alemany, Anna
van Batenburg, Vincent
Moris, Naomi
Blotenburg, Marloes
Vivié, Judith
Baillie-Johnson, Peter
Nichols, Jennifer
Sonnen, Katharina F.
Martinez Arias, Alfonso
van Oudenaarden, Alexander
author_role author
author2 Alemany, Anna
van Batenburg, Vincent
Moris, Naomi
Blotenburg, Marloes
Vivié, Judith
Baillie-Johnson, Peter
Nichols, Jennifer
Sonnen, Katharina F.
Martinez Arias, Alfonso
van Oudenaarden, Alexander
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Embryology
Embryonic stem cells
Mesoderm
RNA sequencing
Synthetic organisms
topic Embryology
Embryonic stem cells
Mesoderm
RNA sequencing
Synthetic organisms
description Gastruloids are three-dimensional aggregates of embryonic stem cells that display key features of mammalian development after implantation, including germ-layer specification and axial organization1-3. To date, the expression pattern of only a small number of genes in gastruloids has been explored with microscopy, and the extent to which genome-wide expression patterns in gastruloids mimic those in embryos is unclear. Here we compare mouse gastruloids with mouse embryos using single-cell RNA sequencing and spatial transcriptomics. We identify various embryonic cell types that were not previously known to be present in gastruloids, and show that key regulators of somitogenesis are expressed similarly between embryos and gastruloids. Using live imaging, we show that the somitogenesis clock is active in gastruloids and has dynamics that resemble those in vivo. Because gastruloids can be grown in large quantities, we performed a small screen that revealed how reduced FGF signalling induces a short-tail phenotype in embryos. Finally, we demonstrate that embedding in Matrigel induces gastruloids to generate somites with the correct rostral-caudal patterning, which appear sequentially in an anterior-to-posterior direction over time. This study thus shows the power of gastruloids as a model system for exploring development and somitogenesis in vitro in a high-throughput manner.
publishDate 2020
dc.date.none.fl_str_mv 2020
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/56609
http://dx.doi.org/10.1038/s41586-020-2024-3
url http://hdl.handle.net/10230/56609
http://dx.doi.org/10.1038/s41586-020-2024-3
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature. 2020;582(7812):405-9
info:eu-repo/grantAgreement/EC/H2020/742225
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Single-cell and spatial transcriptomics reveal somitogenesis in gastruloidsvan den Brink, Susanne C.Alemany, Annavan Batenburg, VincentMoris, NaomiBlotenburg, MarloesVivié, JudithBaillie-Johnson, PeterNichols, JenniferSonnen, Katharina F.Martinez Arias, Alfonsovan Oudenaarden, AlexanderEmbryologyEmbryonic stem cellsMesodermRNA sequencingSynthetic organismsGastruloids are three-dimensional aggregates of embryonic stem cells that display key features of mammalian development after implantation, including germ-layer specification and axial organization1-3. To date, the expression pattern of only a small number of genes in gastruloids has been explored with microscopy, and the extent to which genome-wide expression patterns in gastruloids mimic those in embryos is unclear. Here we compare mouse gastruloids with mouse embryos using single-cell RNA sequencing and spatial transcriptomics. We identify various embryonic cell types that were not previously known to be present in gastruloids, and show that key regulators of somitogenesis are expressed similarly between embryos and gastruloids. Using live imaging, we show that the somitogenesis clock is active in gastruloids and has dynamics that resemble those in vivo. Because gastruloids can be grown in large quantities, we performed a small screen that revealed how reduced FGF signalling induces a short-tail phenotype in embryos. Finally, we demonstrate that embedding in Matrigel induces gastruloids to generate somites with the correct rostral-caudal patterning, which appear sequentially in an anterior-to-posterior direction over time. This study thus shows the power of gastruloids as a model system for exploring development and somitogenesis in vitro in a high-throughput manner.This work was supported by an European Research Council Advanced grant (ERC-AdG 742225-IntScOmics), a Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) TOP award (NWO-CW 714.016.001) and the Foundation for Fundamental Research on Matter, financially supported by NWO (FOM-14NOISE01) to S.C.v.d.B., A.A., V.v.B., M.B., J.V. and A.v.O., a Biotechnology and Biological Sciences Research Council (no. BB/P003184/1), Newton Trust (INT16.24b) and Medical Research Council (MR/R017190/1) grant to A.M.A., a Newnham College Cambridge Junior Research Fellowship to N.M. and a studentship from the Engineering and Physical Sciences Research Council to P.B.-J. The Cambridge Stem Cell Institute is supported by core funding from the Wellcome Trust and Medical Research Council; J.N. was funded by the University of Cambridge and K.F.S. by core funding from the Hubrecht Institute. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. We thank A. Ebbing and M. Betist for the robotized tomo-seq protocol; G. Keller for the Brachyury-GFP cell line; J. Collignon for the Nodal-YFP line; K. Hadjantonakis for the TCF/LEF-mCherry line; S. van den Brink and E. R. Maandag for the E14-IB10 cells; J. Kress and A. Aulehla for the LfngT2AVenus mouse ES cell line; I. Misteli Guerreiro, J. Peterson-Maduro and J. Hoeksma for suggestions for in situ hybridization experiments; W. Thomas, Y. el Azhar, J. Juksar and J. Beumer for reagents and inhibitors; A. de Graaff and A. Stokkermans for help with multiphoton microscopy and analysis of the microscopy data; D. A. Turner for microscopy panels that were used for tomo-seq validation; J. Korving for help with the somite-size measurements in embryos; the Hubrecht FACS facility and R. van der Linden for FACS experiments; Single Cell Discoveries for 10x Genomics scRNA-seq; the Utrecht Sequencing facility for sequencing; and P. Zeller, H. Viñas Gaza, M. Vaninsberghe, V. Bhardwaj and all members of the van Oudenaarden, Sonnen and Martinez Arias laboratories for discussions.Nature Research202320232020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/56609http://dx.doi.org/10.1038/s41586-020-2024-3reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNature. 2020;582(7812):405-9info:eu-repo/grantAgreement/EC/H2020/742225© Springer Nature Publishing AG van den Brink SC, Alemany A, van Batenburg V, Moris N, Blotenburg M, Vivié J, Baillie-Johnson P, Nichols J, Sonnen KF, Martinez Arias A, van Oudenaarden A. Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids. Nature. 2020;582(7812):405-9. DOI: 10.1038/s41586-020-2024-3info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/566092026-06-12T07:21:37Z
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