Stem-cell derived in vitro systems, such as organoids or embryoids, hold great potential for modeling in vivo development. Full control over their initial composition, scalability, and easily measurable dynamics make those systems useful for studying specific developmental processes in isolation. Here we report the formation of gastruloids consisting of mouse embryonic stem cells (mESCs) and extraembryonic endoderm (XEN) cells. These XEN-enhanced gastruloids (XEGs) exhibit the formation of neural epithelia, which are absent in gastruloids derived from mESCs only. By single-cell RNA-seq, imaging, and differentiation experiments, we demonstrate the neural characteristics of the epithelial tissue. We further show that the mESCs induce the differentiation of the XEN cells to a visceral endoderm-like state. Finally, we demonstrate that local inhibition of WNT signaling and production of a basement membrane by the XEN cells underlie the formation of the neuroepithelial tissue. In summary, we establish XEGs to explore heterotypic cellular interactions and their developmental consequences in vitro.

Inclusions in biological membranes may interact via deformations they induce on the shape of that very membrane. Such deformations are a purely physical effect, resulting in nonspecific forces between the inclusions. In this Letter we show that this type of interaction can organize membrane domains and hence may play an important biological role. Using a simple analytical model we predict that membrane inclusions sort according to the curvature they impose. We verify this prediction by both numerical simulations and experimental observations of membrane domains in phase separated vesicles.