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Published September 13, 2022 | Supplemental Material + Published
Journal Article Open

Stem cell-derived synthetic embryos self-assemble by exploiting cadherin codes and cortical tension


Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo.

Additional Information

© The Author(s) 2022, corrected publication 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This work was supported by the Wellcome Trust (207415/Z/17/Z), an European Research Council advanced grant (669198), a National Institutes of Health R01 (HD100456-01A1) grant, the National Institutes of Health Pioneer Award (DP1 HD104575-01), the Tianqiao and Chrissy Chen Institute for Neuroscience and Shurl and Kay Curci Foundation grants to M.Z.-G. E.S.-V. is supported by a Pew Latin America fellowship. M.B. is supported by a Caltech Postdoctoral Fellowship. We thank the Life Science Foundation, members of the M.Z.-G. laboratory and A. Winkel for invaluable comments and suggestions. Contributions. M.B. and M.Z.-G. conceived of the idea. M.B. developed the methodology and performed the investigation. J.D.J., F.H. and M.B. performed the bioinformatics analyses. J.C.-S., S.S. and M.T. performed the modelling. E.S.-V. and M.B. performed the chimera experiments. A.L.C. contributed to experimental design, pilot experiments and schematics. D.-Y.C. and J.C.-S. provided experimental assistance. M.Z.-G. supervised the study. D.M.G. co-supervised the study. M.B., J.C.-S., D.M.G. and M.Z.-G. wrote the paper. Data availability. Previously published scRNA-seq data that were re-analysed here are available under accession code GSE161947. All other data supporting the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper. Code availability. The source code used for the numerical simulations is available on GitHub at https://github.com/jakesorel/CPM_ETX_2022. Competing interests. We would like to disclose that we have filed a patent for this study. The applicants and inventors for this Patent are Min Bao and Magdalena Zernicka-Goetz. The patent was filed on September 2, 2022 by Caltech. This patent pertains to and covers the "Differential adhesion and tension guided formation of stem cell derived embryos". The Patent was filed under the following number: 63/403685. The remaining authors declare no competing interests.


In the version of this article initially published, author Andy L. Cox (Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA) was mistakenly omitted from the author list. The error has been corrected in the HTML and PDF versions of the article.

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Published - s41556-022-00984-y.pdf

Supplemental Material - 41556_2022_984_MOESM10_ESM.xlsx

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August 22, 2023
December 22, 2023