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Journal article
Synthetic embryos complete gastrulation to neurulation and organogenesis
Nature (London), Vol.610, pp.143-153
06/Oct/2022
Abstract
Embryonic stem cells (ESC) can undergo many aspects of mammalian embryogenesis in vitro1-5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem cells (TSCs), extraembryonic endoderm stem cells (XEN), and inducible-XEN cells (iXEN)6-11. Here, we assembled stem-cell derived embryos in vitro from mouse ESCs, TSCs and iXEN cells and showed that they recapitulate whole natural mouse embryo development in utero to day 8.5. Our embryo model displays head-folds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extra-embryonic yolk sac that initiates blood island development. Importantly, we demonstrate that the neurulating embryo model assembled from Pax6 knockout-ESCs aggregated with wild-type TSCs and iXENs recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6 knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse lineages and genes in development. Our results demonstrate the self-organization ability of embryonic and two types of extra-embryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
Details
- Title
- Synthetic embryos complete gastrulation to neurulation and organogenesis
- Creators
- Gianluca Amadei - University of CambridgeCharlotte E Handford - University of CambridgeChengxiang Qiu - University of WashingtonJoachim De Jonghe - University of CambridgeHannah Greenfeld - California Institute of TechnologyMartin Tran - California Institute of TechnologyBeth K Martin - University of WashingtonDong-Yuan Chen - California Institute of TechnologyAlejandro Aguilera-Castrejon - 972WIS_INST___111Jacob H Hanna - 972WIS_INST___111Michael Elowitz - California Institute of TechnologyFlorian Hollfelder - University of CambridgeJay Shendure - University of WashingtonDavid M Glover - California Institute of TechnologyMagdalena Zernicka-Goetz (Corresponding Author) - University of Cambridge
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.610, pp.143-153; 06/Oct/2022
- Number of pages
- 11
- Publisher
- Nature
- Language
- English
- DOI
- https://doi.org/10.1038/s41586-022-05246-3
- Grant note
- We thank all members of the M.Z.-G. laboratory for their suggestions throughout this project, and M. Shahbazi and R. Hadas for help and discussions. This project has been made possible through the following grants to M.Z.-G.: 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. F.H. was supported by the ERC (69566) and the Wellcome Trust (WT108438/C/15/Z). J.D.J. was supported by the Biotechnology and Biological Sciences Research Council. C.E.H. was supported by the Centre for Trophoblast Research, and the Leventis Foundation. A grant from the Paul G. Allen Frontiers Group (Allen Discovery Centre for Cell Lineage Tracing) supported M.Z.-G., M.B.E. and J.S. J.S. is also supported by the National Human Genome Research Institute (1UM1HG011586 to J.S.; R01HG010632 to J.S.) and is an Investigator of the Howard Hughes Medical Institute. M.B.E. is also an Investigator of the Howard Hughes Medical Institute and is supported by an NIH grant (R01 MH116508). H.G. is supported by a Biology and Biological Engineering postdoctoral fellowship from Caltech. D.-Y.C. is supported by a NIH-NRSA postdoctoral fellowship (5F32HD105442). Author contributions -G.A. and C.E.H. designed and carried out the experiments and data analysis. C.Q. performed the tiny-sci-RNA-seq bioinformatic analysis. J.D.J. performed the library preparation for the inDrop scRNA-seq and bioinformatics analysis. H.G. and M.T. performed and analysed the sequential smFISH. B.K.M. performed the library preparation for tiny-sci-RNA-seq. D.-Y.C. collected rat serum. A.A.-C. and J.H.H. provided the gas mixer and pressurising chamber for the last day of ETiX embryoid culture. M.E. supervised the sequential smFISH performed by H.G. and M.T. F.H. supervised the scRNA-seq analysis performed by J.D.J. J.S. supervised the tiny-sci-RNA-seq analysis performed by B.K.M. and C.Q. M.Z.-G., G.A., C.E.H. and D.M.G. wrote the manuscript. M.Z.-G. conceived, planned and supervised the study.
- Record Identifier
- 993401058103596
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