Single-cell Transcriptomics of Postimplantation Embryos: Unveiling Aneuploidy Effects and Lineage Dynamics

Abstract Transfer of aneuploid human embryos, as defined by the presence of > 80% cells with an abnormal chromosome complement, is clinically associated with pregnancy loss or congenital abnormalities. However, the transfer of diploid-aneuploid mosaic embryos can lead to healthy live births, indicating the early presence of aneuploid cells might not necessarily compromise embryo developmental competence. Currently, a comprehensive investigation of the molecular mechanisms determining post-implantation aneuploid cell fates is lacking. Here, we leverage cutting-edge human embryo extended culture techniques and single-cell omics to reveal global ploidy-specific transcriptomic signatures in post-implantation human embryos. We integrate cell demultiplexing and copy number variation calling to characterize diverse embryo cell populations. Differential expression and interactome analyses reveal that different intra-embryo environments facilitate distinct gene expression patterns related to energy expenditure, proteostasis, and DNA damage repair in the aneuploid cells. We observe temporary adaptive stress responses in homogeneous aneuploid embryos, whereas key machinery contributing to cell fitness is suppressed in aneuploid cells from mosaic embryos. Our findings point to a diminished survival advantage in aneuploid cells within post-implantation mosaic embryos, leading to self-correction by aneuploid cell depletion.