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Summary Human periimplantation development requires the transformation of the naive pluripotent epiblast into a polarized epithelium. Lumenogenesis plays a critical role in this process, as the epiblast undergoes rosette formation and lumen expansion to form the amniotic cavity. Here, we present a high-throughput in vitro model for epiblast morphogenesis. We established a microfluidic workflow to encapsulate human pluripotent stem cells (hPSCs) into monodisperse agarose microgels. Strikingly, hPSCs self-organized into polarized epiblast spheroids that could be maintained in self-renewing and differentiating conditions. Encapsulated primed hPSCs required Rho-associated kinase inhibition, in contrast to naive hPSCs. We applied microgel suspension culture to examine the lumen-forming capacity of hPSCs and reveal an increase in lumenogenesis during the naive-to-primed transition. Finally, we demonstrate the feasibility of co-encapsulating cell types across different lineages and species. Our work provides a foundation for stem cell-based embryo models to interrogate the critical components of human epiblast self-organization and morphogenesis., Graphical abstract, Highlights • High-throughput platform to encapsulate human PSCs in agarose microgels • Human PSCs self-organize into epiblast spheroids and undergo lumen expansion • Lumen expansion increases in primed versus naive human PSCs • Monodisperse co-culture of embryonic and extraembryonic stem cells, In this article, Boroviak and colleagues present a high-throughput platform to encapsulate human PSCs into agarose microgels. Human PSCs undergo lumenogenesis and self-organize into rosette-like structures, similar to the human peri-implantation embryo. Their microgel suspension culture regime provides a foundation for the controlled assembly of stem cell-based embryo models in our own species.

The uterus is the organ for embryo implantation and fetal development. Most current models of the uterus are centred around capturing its function during later stages of pregnancy to increase the survival in pre-term births. However, in vitro models focusing on the uterine tissue itself would allow modelling of pathologies including endometriosis and uterine cancers, and open new avenues to investigate embryo implantation and human development. Motivated by these key questions, we discuss how stem cell-based uteri may be engineered from constituent cell parts, either as advanced self-organising cultures, or by controlled assembly through microfluidic and print-based technologies., Bergmann et al. discuss the construction of synthetic uteri to model the earliest stages of human embryogenesis and associated pathologies. They highlight the constituent components from which a synthetic uterus may be engineered, propose a modular approach to assembling synthetic uteri and discuss how these technologies can shed light on implantation failure and uterine pathologies.