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 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-TGF{beta}1 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. HighlightsO_LITELSCs were robustly induced and long-term maintained from TBLCs and early embryos using a newly developed Hippo-YAP/Notch-to-TGF{beta}1 signaling switch strategy C_LIO_LITELSCs resemble E4.5 trophectoderm at the molecular level and generate all trophoblast lineages both in vivo and in vitro functionally C_LIO_LITELSCs can be applied to generate trophoblast organoids containing multiple mature subtypes and a self-renewing ExE-like population C_LIO_LIRosette structure formation that relies on Itgb1 is critical to induce ExE-like progenitors and to eventually form trophoblast organoids C_LI