Transgene directed induction of a human embryo model from pluripotent stem cells

The human embryo undergoes morphogenetic transformations following implantation into the uterus and yet our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Here, we establish a stem cell-derived human post-implantation embryo model comprised of embryonic and extraembryonic tissues. Overexpression of the transcription factors GATA6 and SOX17 or GATA3 and AP2g in hESCs allowed us to generate hypoblast-like and trophoblast-like cells, respectively. We established conditions to combine these extraembryonic-like cells with wildtype embryonic stem cells and promote their self-organization into structures that mimic aspects of the post-implantation human embryo. These aggregates contain an inner pluripotent epiblast-like domain surrounded by both hypoblast- and trophoblast-like tissues. We show that this human embryo stem cell model robustly generates several cell types, including amnion-, extraembryonic mesenchyme- and primordial germ cell-like cells. Using perturbation experiments, we demonstrated that these populations arise in response to BMP signaling. This model also allowed us to identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells. Modulation of the subpopulations in the hypoblast-like compartment demonstrated that these extraembryonic-like cells impact epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, this modular, tractable model of the human embryo that includes both embryonic- and extraembryonic-like cells has the potential to probe key questions of human post-implantation development. single cell 10x multiome (RNA+ATAC) sequencing on transgene-directed human embryo models.