Mouse embryo model derived exclusively from embryonic stem cells undergoes neurulation and heart development
Abstract
Several in vitro models have been developed to recapitulate mouse embryogenesis solely from embryonic stem cells (ESCs). Despite mimicking many aspects of early development, they fail to capture the interactions between embryonic and extraembryonic tissues. To overcome this difficulty, we have developed a mouse ESC-based in vitro model that reconstitutes the pluripotent ESC lineage and the two extraembryonic lineages of the post-implantation embryo by transcription-factor-mediated induction. This unified model recapitulates developmental events from embryonic day 5.5 to 8.5, including gastrulation; formation of the anterior-posterior axis, brain, and a beating heart structure; and the development of extraembryonic tissues, including yolk sac and chorion. Comparing single-cell RNA sequencing from individual structures with time-matched natural embryos identified remarkably similar transcriptional programs across lineages but also showed when and where the model diverges from the natural program. Our findings demonstrate an extraordinary plasticity of ESCs to self-organize and generate a whole-embryo-like structure.
Copyright and License
© 2022 The Author(s). Published by Elsevier Under a Creative Commons license CC BY 4.0 DEED Attribution 4.0 International.
Acknowledgement
The authors would like to thank David Glover for helpful comments, Yoav Mayshar for his assistance with sample collection for scRNA-seq, Netta Reines for technical support with scRNA-seq processing, Joana Cerveira and Mercedes Cabrera Jarana from the flow cytometry facility from the School of the Biological Sciences, University of Cambridge for their assistance in this work, and Jacob Hanna and Alejandro Aguilera-Castrejon for providing a pressurizing chamber that we used for the last day of embryo culture. The grants to M.Z.-G. that supported this work are: NIH Pioneer Award (DP1 HD104575-01), the Allen Discovery Center for Lineage Tracing, European Research Council (669198), the Wellcome Trust (207415/Z/17/Z), Open Philanthropy/Silicon Valley Community Foundation, and Weston Havens Foundation. The grants to Y.S. that supported this work are from the European Research Council (ERC_StG 852865) and the Helen and Martin Kimmel Stem Cell Institute. K.Y.C.L. is supported by the Croucher Foundation and the Cambridge Trust. C.W.G. is supported by a Leverhulm Early Career Research Fellowship. Research in the M.Z.-G. and Y.S. labs is supported by the Schwartz/Reisman Collaborative Science Program.
Contributions
Conceptualization: G.A., M.Z.-G.; Data curation: H.R.; Formal analysis: K.Y.C.L., H.R.; Funding acquisition: Y.S., M.Z.-G.; Investigation: K.Y.C.L., C.W.G.; Methodology: K.Y.C.L., R.H.; Software: H.R.; Visualization: K.Y.C.L., H.R.; Supervision: Y.S., M.Z.-G.; Writing: K.Y.C.L., H.R., Y.S., and M.Z.-G.
Data Availability
- scRNA-seq data have been deposited at ArrayExpress and are publicly available as of the date of publication. Accession number is listed in the key resources table.
- Code used in the study has been deposited at Zenodo and is publicly available as of the date of publication. DOI is listed in the key resources table.
- Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Conflict of Interest
M.Z.-G. is an advisory board member of Cell Stem Cell. M.Z.-G. and G.A. wish to declare the filing of a patent on May 5th, 2022 by Caltech and the University of Cambridge on the "Generation of synthetic embryos from multiple stem cell types." The patent was filed under the following numbers: CIT File No.: CIT-8826-P and Serial Number: 63/344,251.
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Additional details
- PMCID
- PMC9648694
- National Institutes of Health
- HD104575-01
- European Research Council
- 669198
- Wellcome Trust
- 207415/Z/17/Z
- Open Philanthropy Project
- Silicon Valley Community Foundation
- European Research Council
- 852865
- Croucher Foundation
- Leverhulme Trust
- Caltech groups
- Division of Biology and Biological Engineering