In vitro attachment and symmetry breaking of a human embryo model assembled from primed embryonic stem cells

Highlights

• Assembloid of intra- and xEM cells as a strategy to model the human post-attached embryo

• hESCs on soft substrates exposed to BMP4 produce cells with mixed xEM signatures

• Co-culture of intra- and xEM cells forms embryo-like structures and attaches in vitro

• xEM-like cells deliver signals that break the anteroposterior symmetry in the epiblast

Summary

Our knowledge of the molecular mechanisms surrounding human embryo implantation and gastrulation is lacking, largely due to technical and ethical limitations of experimenting with human embryos. Alternatives to human embryos have been reported, in which 3D clusters of embryonic stem cells are differentiated in a stepwise manner to model aspects of human embryogenesis. Yet it remains challenging to model the events past attachment. We propose a strategy of modeling the post-attachment human embryo by assembling a pre-formed polarized epithelial epiblast and extraembryonic cells, allowing them to self-organize into a structure that mimics the dish-attached human embryo. The model attaches in vitro and, in the absence of exogenous morphogens, breaks anteroposterior symmetry, giving rise to early gastrulation cell types. Our assembloid approach enables in a modular way to upgrade or exchange extraembryonic tissues to access more advanced stages of post-attachment development while complying with ethical policies.