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 significant challenge in developmental and synthetic biology. In this study, we established conditions that enabled the continuous ex utero development of mouse embryo models (EMs), starting solely from the very beginning of chemically induced totipotent-like stem cells (ciTotiSCs) 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, hematopoiesis and early organogenesis, closely resembling E8.5 natural embryos (NEs). Furthermore, extended culture led to the development of functional cardiac tissues in ciToti-EMs, highly comparable to that 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 new model for investigating mammalian embryonic development and opens new avenues for creating multicellular organisms from non-germline cells.