Modelling mouse embryogenesis from chemically induced totipotent stem cells

The ability to faithfully initiate embryogenesis from a single, induced non-germline cell type, akin to the totipotent blastomeres, remains a considerable challenge in developmental and synthetic biology^1-14. Here we established conditions that enable the continuous ex utero development of mouse embryo models (EMs), starting solely from the chemically induced totipotent-like stem cells (ciTotiSCs)¹⁵ and spanning the pre-implantation morula, blastocysts and post-gastrulation stages with both embryonic and extraembryonic compartments. These ciTotiSCs self-organized into blastocyst-like structures that closely resembled natural blastocysts in both morphology and lineage segregation. The resulting ciTotiSC-derived EMs (ciToti-EMs) successfully progressed through key developmental milestones, including gastrulation, embryonic axis formation, haematopoiesis and early organogenesis, closely resembling embryonic day 8.5 (E8.5) natural embryos (NEs). Furthermore, extended culture led to the development of functional cardiac tissues in ciToti-EMs, highly comparable to those of E10.5 NEs. These findings demonstrate an extraordinary ability of a single induced cell type, ciTotiSCs, to autonomously recapitulate the complete spectrum of early mouse embryogenesis. Our ciToti-EM system provides a powerful model for investigating mammalian embryonic development and opens new avenues for creating multicellular organisms from non-germline cells.