Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures.

Abstract

Embryonic stem (ES) cells can be incorporated into the developing embryo and its germ line but when cultured alone, their ability to generate embryonic structures is restricted. They can interact with trophoblast stem (TS) cells to generate structures that break symmetry and specify mesoderm, but their development is limited as the epithelial-mesenchymal-transition (EMT) of gastrulation cannot occur. Here we describe a system that, for the first time, allows assembly of mouse ES, TS and extra-embryonic-endoderm (XEN) cells into structures that acquire the embryo’s architecture with all distinct embryonic and extra-embryonic compartments. Strikingly, such embryo structures develop to undertake EMT, leading to mesoderm and then definitive endoderm specification. Spatial transcriptomic analyses demonstrate that these morphological transformations are underpinned by gene-expression patterns characteristic of gastrulating embryos. This demonstrates the remarkable ability of three stem cell types to self-assemble in vitro into gastrulating embryo structures undertaking spatio-temporal events of the gastrulating mammalian embryo.