Mosaicism and Aneuploidy Lead to Gradual Loss of Biochemical Identity and Induce Apoptosis in Human Blastocysts

Complex aneuploidy triggers autophagy and p53-mediated apoptosis and impairs the second lineage segregation in human preimplantation embryos

“…Finally, we found that in those embryos that had already undergone the second lineage segregation event, the aneuploid embryos had a significantly lower ratio of PrE (GATA4-positive) to EPI (OCT4-positive/GATA4-negative) cells than euploid embryos. Our findings are in line with the upregulation of the PrE marker SOX17 that has been recently found by gene-expression analysis of euploid and low-and high level mosaic human embryos (Martin et al, 2023 ). Further, we observed that this effect was dosage-dependent, with embryos with larger gene-dosage imbalances showing significantly lower cell numbers in the TE and PrE than euploid embryos or embryos with lower gene-dosage imbalances.…”

“…undergoing apoptosis. These results are in line with the findings of Victor et al (Victor et al, 2019 ), where the TE of mosaic and aneuploid embryos showed increased levels of apoptosis, and the recent RNAsequencing of TE and ICM samples of mosaic human embryos (Martin et al, 2023 ). Mosaic TE cells showed disrupted regulation of apoptosis while the ICM showed primarily deregulated mitochondrial function.…”

“…Overall, our gene-expression results are in line with previously published RNA-sequencing studies on aneuploid human embryonic cells that identified transcriptional signatures consistent with DNA damage (Vera-Rodriguez et al, 2015 ;Licciardi et al, 2018 ;Fuchs Weizman et al, 2019 ), alteration of cell proliferation (Starostik et al, 2020 ;Maxwell et al, 2022 ;Martin et al, 2023 ), the cell cycle (Vera-Rodriguez et al, 2015 ;Licciardi et al, 2018 ;Fuchs Weizman et al, 2019 ;Starostik et al, 2020 ;Martin et al, 2023 ), deregulation of autophagy (Licciardi et al, 2018 ;Sanchez-Ribas et al, 2019 ), p53 signalling (Licciardi et al, 2018 ) and apoptosis (Licciardi et al, 2018 ;Groff et al, 2019 ;Sanchez-Ribas et al, 2019 ;Maxwell et al, 2022 ;Martin et al, 2023 ). However, when comparing our dataset of differentially expressed genes to these studies, we only found modest overlaps at the level of individual genes.…”

“…Taken together, our results suggest that while the same pathways appear to be activated in human and mouse embryos with complex aneuploidy, human embryos have a different response when it comes to the downstream effect of these pathways in the different cell lineages. While the mouse readily depletes aneuploid cells by apoptosis specifically from the embryonic lineage before implantation (Bolton et al, 2016 ;Singla et al, 2020 ), in the preimplantation human embryo, apoptosis appears to be more active in the TE, as also seen by others (Victor et al, 2019 ;Martin et al, 2023 ). The results suggest that in the human embryo, undifferentiated pluripotent cells have a different response to aneuploidy-induced cellular stress than the neighbouring differentiated cells.…”

Chromosomal Aberrations as a Biological Phenomenon in Human Embryonic Development

“…Decisions about the fate of mosaic embryos identified at IVF clinics are still made “doubtfully” due to the lack of sufficient fundamental knowledge. From a biological point of view, the developmental potential of mosaic embryos may depend both on the proportion and location of abnormal cells and on the numbers of chromosomes involved in mosaicism [ 6 , 20 , 76 , 77 , 78 ]. However, data from different research groups vary, probably, due to the effect of laboratory and technical factors on the actual biological events associated with chromosomal mosaicism.…”