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Stem cell-derived mouse embryos develop within an extra-embryonic yolk sac to form anterior brain regions and a beating heart

Amadei, Gianluca and Handford, Charlotte E. and De Jonghe, Joachim and Hollfelder, Florian and Glover, David and Zernicka-Goetz, Magdalena (2022) Stem cell-derived mouse embryos develop within an extra-embryonic yolk sac to form anterior brain regions and a beating heart. . (Unpublished)

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Embryo-like structures generated from stem cells can achieve varying developmental milestones, but none have been shown to progress through gastrulation, neurulation, and organogenesis. Here, we show that ETiX mouse embryos, established from embryonic stem cells aggregated with trophoblast stem cells and inducible extraembryonic endoderm stem cells, can develop through gastrulation and beyond to undertake neural induction and generate the progenitors needed to create the entire organism. The head-folds of ETiX embryos show anterior expression of Otx2, defining forebrain and midbrain regions that resemble those of the natural mouse embryo. ETiX embryos also develop beating hearts, trunk structures comprising a neural tube and somites, tail buds containing neuromesodermal progenitors and primordial germ cells, and gut tubes derived from definitive endoderm. A fraction of ETiX embryos show neural tube abnormalities, which can be partially rescued by treatment with the metabolically active form of folic acid, reminiscent of common birth defects and therapies in humans. Notably, ETiX embryos also develop a yolk sac with blood islands. Overall, ETiX embryos uniquely recapitulate natural embryos, developing further than any other stem-cell derived model, through multiple post-implantation stages and within extra-embryonic membranes.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Hollfelder, Florian0000-0002-1367-6312
Glover, David0000-0003-0956-0103
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. We would like to thank all the members of MZG lab for their helpful comments throughout this project. This project has been made possible through the following grants to MZG: NIH Pioneer Award (DP1 HD104575-01), European Research Council (669198), the Wellcome Trust (207415/Z/17/Z), Open Philanthropy/Silicon Valley Community Foundation and Weston Havens Foundation and the Centre for Trophoblast Research. FH was supported by the ERC (69566) and the Wellcome Trust (); and JdJ thanks the BBSRC DTP for a studentship. CEH was supported by the Centre for Trophoblast Research, and the Leventis Foundation. Contributions. GA and CEH designed and carried out the experiments and data analysis. JdJ performed the library preparation for single cell RNA-sequencing and bioinformatics analysis. FH supervised the single cell RNA-sequencing analysis. MZG, GA, CEH wrote the manuscript with DG. MZG conceived and supervised the study. Materials Availability. All unique/stable reagents generated in this study are available from the Lead Contact with a completed Materials Transfer Agreement. Code Availability. Any custom code generated in this study is available upon request. The authors have declared no competing interest.
Funding AgencyGrant Number
NIHDP1 HD104575-01
European Research Council (ERC)669198
Wellcome Trust207415/Z/17/Z
Open PhilanthropyUNSPECIFIED
Silicon Valley Community FoundationUNSPECIFIED
Weston Havens FoundationUNSPECIFIED
European Research Council (ERC)695669
Biotechnology and Biological Sciences Research Council (BBSRC)UNSPECIFIED
Centre for Trophoblast ResearchUNSPECIFIED
Leventis FoundationUNSPECIFIED
Record Number:CaltechAUTHORS:20220803-224696000
Persistent URL:
Official Citation:Stem cell-derived mouse embryos develop within an extra-embryonic yolk sac to form anterior brain regions and a beating heart Magdalena Zernicka-Goetz, Gianluca Amadei, Charlotte E Handford, Joachim De Jonghe, Florian Hollfelder, David Glover bioRxiv 2022.08.01.502375; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:116064
Deposited By: George Porter
Deposited On:03 Aug 2022 19:32
Last Modified:03 Aug 2022 19:32

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