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.
Additional Information
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. Data and code 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.Additional details
- PMCID
- PMC9648694
- Eprint ID
- 117995
- DOI
- 10.1016/j.stem.2022.08.013
- Resolver ID
- CaltechAUTHORS:20221122-564647900.8
- DP1 HD104575-01
- NIH
- Allen Discovery Center for Lineage Tracing
- 669198
- European Research Council (ERC)
- 207415/Z/17/Z
- Wellcome Trust
- Open Philanthropy
- Silicon Valley Community Foundation
- Weston Havens Foundation
- 852865
- European Research Council (ERC)
- Helen and Martin Kimmel Stem Cell Institute
- Croucher Foundation
- Cambridge Trust
- Leverhulme Trust
- Schwartz/Reisman Collaborative Science Program
- Created
-
2022-12-07Created from EPrint's datestamp field
- Updated
-
2022-12-07Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering