Reconstitution of Human Peri-Implantation Embryogenesis With Integrated Stem Cell-Based Embryo Models

Studies of cultured human embryos have provided insights into human peri-implantation embryogenesis but are limited by ethical and technical constraints. Here we assembled a 3D integrated embryo model (IEM) using naive human embryonic stem cells (hESCs) and hESC-derived proliferating trophoblasts. By comparing phenotypic cell fate and comprehensive single-cell transcriptome of IEMs with 3D-cultured human embryos, we reveal that IEMs with embryonic and extra-embryonic cell types mimic developmental landmarks and 3D morphological features of natural human post­­­ ­­-implantation embryos, including pluripotent state transitions, epithelial-mesenchymal transition, anterior-posterior axis formation, amniotic cavity, yolk sac, bilaminar embryonic disc, extra-embryonic mesenchyme, primitive streak and primordial germ cells. Using IEMs, we unravel composition and gene expression patterns of embryonic lineages, and that trophoblasts secret WNT, BMP and TGFβ/Activin signals to instruct post-implantation embryogenesis . Our findings show that IEMs provide a scalable and tractable model for decoding regulatory mechanisms of human peri-implantation embryogenesis.