Mapping mammalian placental formation and implantation transitions with single-cell transcriptomics and live imaging

Implantation remains the most inaccessible stage of mammalian development. Consequently, we know remarkably little about how the embryo coordinates the cellular transitions that establish the body plan and initiate placental formation, despite this being the period when most pregnancies are lost. Here we combine single-cell transcriptomics, live imaging and functional experiments to define these transitions at cellular resolution. Our results identify an intermediate state bridging naive and primed pluripotency in the embryonic lineage, trace anterior-posterior axis specification origins in the extraembryonic endoderm, and reveal trophectoderm bifurcation into distinct placental progenitors. Strikingly, we find that the placenta arises from two sources: the classically recognized polar trophectoderm and a previously unrecognized population of mural trophectoderm that migrates from the polar-mural border. Human mural trophectoderm shows similar region-specific behaviour and may include invasive-trophoblast-biased progenitors. These findings open new directions for improving stem-cell-derived embryo models and uncovering the early determinants of pregnancy success.