An inducible model of human post-implantation development derived from primed and naive stem cells

Early post-implantation human development is poorly understood due to limited access to natural embryos. Integrated stem cell-based embryo models (SCBEMs) offer an alternative, but current models face challenges in reproducibility, efficiency, and genomic stability. Here, we developed inducible SCBEMs (iSCBEMs) by combining primed human pluripotent stem cells (hPSCs) with transgene-induced extraembryonic cells derived from naive hPSCs. iSCBEMs recapitulate several key features of early post-implantation development, including amniotic-, yolk sac-, and chorionic-like cavity formation, differentiation of syncytiotrophoblast-like cells forming lacunae, bilaminar disk formation, anterior-posterior axis establishment, and early gastrulation. Single-cell RNA sequencing revealed that iSCBEMs recapitulate key cell types and developmental transitions characteristic of Carnegie stage 5–6 (CS5–CS6) embryos. We further traced the origins of amnion-, yolk sac endoderm-, and extraembryonic mesoderm-like cells, providing insights into their developmental trajectories. Although imperfect, human iSCBEMs represent a robust and valuable model for studying early post-implantation development, overcoming the limitations of natural embryo accessibility.