Synthetic embryos complete gastrulation to neurulation and organogenesis

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.
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 (WT108438/C/15/Z); JdJ was supported by the Biotechnology and Biological Sciences Research Council. CEH 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 MZG, ME and JS. JS 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. HG is supported by a Biology and Biological Engineering postdoctoral fellowship from Caltech. DY is supported by a NIH-NRSA postdoctoral fellowship (5F32HD105442)