High-Fidelity, Efficient Human Post-Implantation Embryo Models Generated by STAT3-Induced Cell Plasticity [ATAC-Seq]

Human embryo models hold great promise as surrogates for studying development and as platforms for medicine. However, existing models lack efficiency and fidelity in replicating post-implantation stages. Here we asked if STAT3 could reprogram pluripotent stem cells (PSCs) into all blastocyst fates and generate embryo models. Using a medium for enhanced STAT3 activity (SAM), PSCs rapidly reprogram into intermediates that specify all blastocyst fates: hypoblast, trophectoderm and naïve-pluripotent epiblast, within 60 hours. Strikingly, following dissociation of SAM-treated PSCs on 60 or 120 hours and subsequent 3D assembly, structures resembling post-implantation embryos develop within 4 days, with up to 52.41±8.92% efficiency. These exhibited a bilaminar disc-like structure, including epiblast and hypoblast discs, yolk-sac and amniotic cavities, mesenchyme tissue, chorionic cavity, and trophoblast. The STAT3-mediated embryo models (stEMs) also demonstrate unparalleled molecular alignment with the Carnegie Stage 6-7 embryo reference. Thus, stEMs offer state-of-the-art models for advancing our understanding of post-implantation human embryogenesis.