Synthetic embryos complete gastrulation to neurulation and organogenesis - Nature.com

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Abstract

Embryonic stem cells (ESC) can undergo many aspects of mammalian embryogenesis in vitro^1–5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem cells (TSCs), extraembryonic endoderm stem cells (XEN), and inducible-XEN cells (iXEN)^6–11. Here, we assembled stem-cell derived embryos in vitro from mouse ESCs, TSCs and iXEN cells and showed that they recapitulate whole natural mouse embryo development in utero to day 8.5. Our embryo model displays head-folds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extra-embryonic yolk sac that initiates blood island development. Importantly, we demonstrate that the neurulating embryo model assembled from Pax6 knockout-ESCs aggregated with wild-type TSCs and iXENs recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6 knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse lineages and genes in development. Our results demonstrate the self-organization ability of embryonic and two types of extra-embryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.

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Author information

Author notes

1. Gianluca Amadei

   Present address: Department of Biology, University of Padua, Padua, Italy

2. Joachim De Jonghe

   Present address: Francis Crick Institute, London, UK

3. These authors contributed equally: Gianluca Amadei, Charlotte E. Handford

Authors and Affiliations

1. Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK

   Gianluca Amadei, Charlotte E. Handford & Magdalena Zernicka-Goetz

2. California Institute of Technology, Division of Biology and Biological Engineering, 1200 E. California Boulevard, Pasadena, CA, USA

   Gianluca Amadei, Charlotte E. Handford, Hannah Greenfeld, Martin Tran, Dong-Yuan Chen, Michael Elowitz, David M. Glover & Magdalena Zernicka-Goetz

3. Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK

   Charlotte E. Handford & Magdalena Zernicka-Goetz

4. Department of Genome Sciences, University of Washington, Seattle, WA, USA

   Chengxiang Qiu, Beth K. Martin & Jay Shendure

5. Department of Biochemistry, University of Cambridge, Cambridge, UK

   Joachim De Jonghe & Florian Hollfelder

6. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

   Alejandro Aguilera-Castrejon & Jacob H. Hanna

7. Allen Discovery Center for Cell Lineage Tracing, Seattle, WA, USA

   Michael Elowitz, Jay Shendure & Magdalena Zernicka-Goetz

8. Brotman Baty Institute for Precision Medicine, Seattle, WA, USA

   Jay Shendure

9. Howard Hughes Medical Institute, Seattle, WA, USA

   Jay Shendure

Authors

1. Gianluca Amadei
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2. Charlotte E. Handford
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3. Chengxiang Qiu
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4. Joachim De Jonghe
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5. Hannah Greenfeld
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6. Martin Tran
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7. Beth K. Martin
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8. Dong-Yuan Chen
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9. Alejandro Aguilera-Castrejon
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10. Jacob H. Hanna
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11. Michael Elowitz
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12. Florian Hollfelder
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13. Jay Shendure
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14. David M. Glover
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15. Magdalena Zernicka-Goetz
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Corresponding author

Correspondence to Magdalena Zernicka-Goetz.

Supplementary information

Reporting Summary

Supplementary Table 1

Gene Ontology of E7.5 embryos. Gene ontology analysis of the differentially expressed genes enriched in natural embryos cultured from E6.5 to E7.5 ex utero and analysed by tiny-sci..

Supplementary Table 2

Gene Ontology of ETiX6-embryoids. Gene ontology analysis of the differentially expressed genes enriched in ETiX-embryoids analysed at day 6 of development by tiny-sci.

Supplementary Table 3

Gene Ontology of E8.5 embryos. Gene ontology analysis of the differentially expressed genes enriched in natural embryos cultured from E6.5 to E8.5 ex utero and analysed by tiny-sci.

Supplementary Table 4

Gene Ontology of ETiX8-embryoids. Gene ontology analysis of the differentially expressed genes enriched in ETiX-embryoids analysed at day 8 of development by tiny-sci.

Supplementary Table 5

Gene Ontology of Extraembryonic endoderm. Gene Ontology analysis of the genes enriched in “Early VE” cell populations in the extraembryonic endoderm subcluster of ETiX-embryoids.

Supplementary Table 6

Gene Ontology of older cell clusters in Extraembryonic endoderm. Gene Ontology analysis of the genes enriched in “Differentiated yolk sac” cell populations of ETiX-embryoids.

Supplementary Table 7

Antibody Table. A table of the antibodies utilised in this study..

Supplementary Table 8

Oligonucleotide Table. A table of the oligonucleotides utilised in this study.

Supplementary Video 1

Live imaging of ETiX8 embryo showing beating heart. n=11 structures from 4 independent experiments.

Supplementary Video 2

Live imaging of ETiX8 embryo showing beating heart. n=11 structures from 4 independent experiments.

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Amadei, G., Handford, C.E., Qiu, C. et al. Synthetic embryos complete gastrulation to neurulation and organogenesis. Nature (2022). https://ift.tt/KXurzFa

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• Received: 09 November 2021

• Accepted: 17 August 2022

• Published: 25 August 2022

• DOI: https://ift.tt/KXurzFa

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