Capturing trophectoderm-like stem cells enables step-wisely remodeling of placental development

The trophectoderm produced from totipotent blastomeres initiates trophoblast development, while placental deficiencies can cause pregnancy disorders. Yet, a culture system that fully recapitulates the entire placenta development is still lacking, greatly limiting related studies. Here, we captured mouse trophectoderm-like stem cells (TELSCs), which can give rise to all trophoblast lineages and can be applied to generate trophoblast organoids. We achieved the induction and maintenance of TELSCs from totipotent blastomere-like stem cells or early embryos through a Hippo-YAP/Notch-to-TGFβ1 signaling switch. At the molecular level, TELSCs resemble E4.5 trophectoderm and are distinct from all previously known trophoblast-like stem cells. Functionally, TELSCs can generate all trophoblast lineages in both teratoma and chimera assays. We further applied TELSCs to generate trophoblast organoids containing various mature trophoblasts and a self-renewing extraembryonic ectoderm (ExE)-like progenitor population. Interestingly, we observed transiently formed rosette-like structures that rely on Itgb1, which are essential to induce ExE-like progenitors and to generate organoids eventually. Thus, the capture of TELSCs enables comprehensive insights into placental development.