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Embryonic stem (ES) cells 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 (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6-11. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds 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 extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from ?x6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion ofthe neural tube that occurs in natural, ubiquitous ?x6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
In natural development, the zygote develops into the epiblast, which will form the organism; the extraembryonic visceral endoderm (VE), which contributes to the yolk sac; and the extraembryonic ectoderm (ExE), which contributes to the placenta. Stem cells corresponding to these three lineages offer the possibility to completely regenerate the mammalian organism from multiple components, instead of from a single totipotent zygote.
ES cells, which are derived from the epiblast, show a remarkable ability to form embryo-like structures upon aggregation and, when embedded in Matrigel, can be induced to form trunk-like structures with somites, a neural tube and a gut1-5. Although neural development can be promoted in such 'gastruloids' by inhibiting the initial burst of Wnt activity, they do not accurately replicate gastrulation movements, nor do they represent the complete anatomy of natural embryos. Other model embryoids generated from ES cells aggregated with an ectopic morphogen signalling centre can develop the posterior midbrain, neural tube, cardiac tissue and...