Reconstituting epiblast–extraembryonic endoderm interactions restores anterior–ventral patterning in mouse stem cell–based embryo models

During mouse embryogenesis, the interactions between the epiblast and extraembryonic endoderm are critical for germ layer specification and body plan development. Gastruloids recapitulate aspects of gastrulation in the absence of morphogenic signals from the extraembryonic environment. This favors a predominantly posteriorized and dorsalized phenotype with a limited representation of embryonic lineages. Here, we develop and employ a co-aggregation (aggregoid) approach combining embryonic and extraembryonic endoderm-like cells to mimic spatial interactions in developing mouse embryos. The obtained embryo models show the appearance of node and notochord, enriched endoderm populations, increased mesoderm diversity including cardiopharyngeal lineages and vascular endothelium in an overall anteriorized and ventralized phenotype. The work delineates a versatile strategy for refining stem cell-based embryo models to achieve specific morphotypes.