Researchers at Peking University has developed a "two-step" signaling switch—transitioning from Hippo-YAP/Notch to TGFβ1 pathways—to capture and stably maintain a novel stem cell state termed Trophectoderm-Like Stem Cells (TELSCs). These cells, derived from totipotent blastomere-like cells (TBLCs) or 8-cell embryos, precisely mirror the transcriptomic and epigenetic landscape of the E4.5 pre-implantation trophectoderm. Functionally, TELSCs exhibit extraordinary developmental plasticity; in chimeric assays, they contribute to all eight known trophoblast lineages at single-cell resolution. Furthermore, TELSCs efficiently assemble into 3D trophoblast organoids (TELSC-TOs) that recapitulate the coupled self-renewal and multi-lineage differentiation characteristic of the native placenta.

The study also identifies a critical morphogenetic prerequisite for organogenesis: the transient formation of a rosette-like structure governed by the integrin β1 signaling factor Itgb1. Within the first 48 hours of organoid formation, TELSCs reorganize into polarized rosettes with markers such as PARD6B and PODXL localized at the lumen center, mimicking the symmetry-breaking events of the E5.5–6.5 extraembryonic ectoderm in vivo. Disrupting this structure via Itgb1 knockdown leads to a failure in progenitor induction and subsequent organoid collapse. The comparative inability of traditional trophoblast stem cells (TSCs) to form these rosettes underscores the high fidelity of the TELSC-TO model. This platform offers a powerful tool for investigating the early molecular origins of pregnancy disorders such as miscarriage and preeclampsia.
DOI: 10.1093/procel/pwaf098