Transgene directed induction of a stem cell-derived human embryo model

Abstract The human embryo undergoes morphogenetic transformations following implantation into the uterus, yet our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo . Stem cell-derived models of the embryo are important tools to interrogate developmental events and tissue-tissue crosstalk during these stages 1 . Here, we establish a human post-implantation embryo model comprised of embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cells generated by transcription factor overexpression with wildtype embryonic stem cells and promote their self-organization into structures that mimic aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by hypoblast-and trophoblast-like tissues. We demonstrate that these inducible human embryoids robustly generate several cell types, including amnion, extraembryonic mesenchyme, and primordial germ cell-like cells 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 2 . Modulation of the subpopulations in the hypoblast-like compartment demonstrated that extraembryonic-like cells impact epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, we present a modular, tractable, integrated 3 model of the human embryo that will allow us to probe key questions of human post-implantation development, a critical window when significant numbers of pregnancies fail.