Embryo quality control via lineage-specific aneuploid cell elimination in embryos and stem cell-derived embryo models.

Abstract

Aneuploidy is frequent in human pre-implantation embryos and a leading cause of early pregnancy loss, yet is rarely observed at birth, implying robust embryonic surveillance. Here we define how this surveillance operates after implantation using an integrated, three-lineage stem cell-derived embryo model that recapitulates the epiblast (EPI), visceral endoderm (VE), and extraembryonic ectoderm (ExE). Seeding of aneuploid cells into each lineage independently reveals lineage-specific fates: aneuploid cells are selectively depleted from EPI and VE but persist within ExE. Live imaging captures their removal by apoptosis or physical extrusion. Single-cell RNA sequencing shows p53 activation and Myc repression in aneuploid cells, and pathway perturbations modulate their clearance, confirming causality. Together, these findings demonstrate a post-implantation, lineage-restricted quality-control program that eliminates aneuploid cells from the embryo proper while permitting extraembryonic tolerance. They also establish integrated embryo models as a tractable platform to dissect the molecular logic of developmental quality control.