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. Overall design: We reprogram primed hPSCs to simultaneously acquire epiblast-like, hypoblast-like and trophectoderm-like fates by exploiting STAT3 activation and TGFb inhibition. Further assembling the reprogrammed intermediates or products in 3D and cultureing the aggregates in suspension in in vitro culture medium, they self-organize into embryo like structures resembling to Carnegie Stage 6-7 human embryo.