Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro
Abstract
Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, we combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, we show that embryogenesis of ESC- and TSC-derived embryos—ETS-embryos—depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Our study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.
Additional Information
© 2017 American Association for the Advancement of Science. 9 October 2016; accepted 17 February 2017. Published online 2 March 2017 We are grateful to D. Glover, M. Shahbazi, S. Vuoristo, and F. Antonica for helpful feedback on the manuscript; A. Hupalowska for drawing models (Figs. 1A, 2I, and 8) and G. Recher for 3D rendering (Fig. 1, B and D); the creators of the "Bioemergences" platform for providing image analysis tools; and V. Kuskoff, A. Surani, and B. Herrmann for providing T:GFP ESCs and Stella:GFP ESCs. We are grateful to the Wellcome Trust and ERC for supporting this work. S.E.H. and C.K. are both supported by Biotechnology and Biological Sciences Research Council doctoral training partnership studentships. B.S. is supported by the International Research Fellowship Program 2214/A from Scientific and Technological Research Council of Turkey, and M.Z.-G. by the Wellcome Trust. S.E.H. served as an intern in the Cambridge, UK, office of Science/AAAS. M.Z.-G. and S.E.H. are inventors on a patent application (1615343.9) submitted by Cell Guidance Systems, in which the University of Cambridge and the Wellcome Trust are beneficiaries, that covers the method and medium composition used to generate "stem cell–derived embryos." S.E.H. and B.S. carried out experiments and data analysis on ETS-embryos. N.C. and C.K. carried out experiments on natural embryos. M.Z.-G. conceived and supervised the study and wrote the paper with the help of S.E.H. and B.S.Attached Files
Supplemental Material - Harrison.SM.pdf
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Additional details
- Eprint ID
- 94534
- DOI
- 10.1126/science.aal1810
- Resolver ID
- CaltechAUTHORS:20190405-170314754
- Wellcome Trust
- European Research Council (ERC)
- Biotechnology and Biological Sciences Research Council (BBSRC)
- 2214/A
- Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK)
- Created
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2019-04-09Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field