Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism

Singla, Shruti; Iwamoto-Stohl, Lisa K.; Zhu, Meng; Zernicka‐Goetz, Magdalena

doi:10.1038/s41467-020-16796-3

Cited by 145 publications

(129 citation statements)

References 57 publications

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“…3g, h). This result could also be explained by selective elimination of the aneuploid cells by programmed cell death as the embryo developed beyond day 5, as previously shown to occur in mouse embryos 26,30 . Alternatively, if the aneuploid cells were restricted to the mural trophoblast these cells could have been removed during the biopsy procedure at day 5.…”

Section: (Supplementarysupporting

confidence: 53%

“…In this regard, the fate of aneuploid cells in mosaic human embryos remains unknown. Previous results from our lab have shown that in mouse embryos aneuploid cells in the embryonic epiblast present a higher rate of apoptosis than aneuploid cells in the extra-embryonic tissues 26,30 . These results rely on inducing aneuploidy by the drug reversine, which can cause chaotic aneuploidies 26 .…”

Section: Discussionmentioning

confidence: 67%

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Developmental potential of aneuploid human embryos cultured beyond implantation

Shahbazi

Wang²,

Tao³

et al. 2020

Nat Commun

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Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.

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Section: (Supplementarysupporting

confidence: 53%

Section: Discussionmentioning

confidence: 67%

Developmental potential of aneuploid human embryos cultured beyond implantation

Shahbazi

Wang²,

Tao³

et al. 2020

Nat Commun

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“…They found that aneuploid cells in the fetal lineage (i.e., inner cell mass producing the fetus) were eliminated by apoptosis, while those in the placental lineage (i.e., the TE) did show proliferative defects though survived. In a recently published study from the same group, Singla et al [18] have demonstrated that aneuploid cells are preferentially eliminated from the embryonic lineage in a p53-dependent process involving both autophagy and apoptosis before, during and after implantation. It might be therefore argued, that early embryos development could be controlled by the establishment of a cell death program to ensure the elimination of damaged cells [19], while maintaining an optimal balance between survival and apoptotic signals.…”

Section: Introductionmentioning

confidence: 99%

Do human embryos have the ability of self-correction?

Orvieto

Shimon

Rienstein

et al. 2020

Reprod Biol Endocrinol

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Human embryogenesis frequently coinciding with cell division mistakes contributing to pervasive embryonic aneuploidy/mosaicism. While embryo self-correction was elegantly demonstrated in mouse models, human studies are lacking. Here we are witness to human embryos ability to eliminate/expel abnormal blastomeres as cell debris/fragments. Each blastocyst and its corresponding debris were separated and underwent whole genome amplification. Seven of the 11 pairs of blastocysts and their corresponding cell debris/fragments revealed discordant results. Of the 9 euploid blastocysts, four showed euploid debris, while in the others, the debris were aneuploid. In the remaining pairs, the debris showed additional aneuploidy to those presented by their corresponding blastocyst. The observed ability of human embryos to self-correction doubts many invasive and non-invasive preimplantation testing for aneuploidy at the blastocyst stage, rendering high rate of false positive (discarding “good” embryos) by identifying the cell-free DNA originated from the expelled cell debris, as aneuploidy/mosaic blastocyst.

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“…A mouse model demonstrated that aneuploid cells can be eliminated during embryo development either via apoptosis in inner cell mass or a prolonged cell cycle in trophectoderm cells (Bolton et al 2016). Apoptosis of aneuploid cells in mouse embryos is linked with autophagy-mediated pathways; however, whether the same 'rescue' mechanisms operate in human embryos remains to be determined (Singla et al 2020).…”

Section: Consequence Of Chromosomal Mosaicism On Embryo Developmentmentioning

confidence: 99%

“…Understanding the fate and effect of aneuploid cells in an environment of euploid cells during preimplantation development (Bolton et al 2016, Singla et al 2020 and beyond (Shahbazi et al 2016, Popovic et al 2019 will be of particular relevance to improve current PGT-A decision making when only mosaic blastocysts are available. Development and advances in single-cell omics technologies have revolutionized our understanding of cellular heterogeneity and gene expression regulation in health and disease.…”

Section: Human Embryo Development Uncovered By Single-cell Rna-seqmentioning

confidence: 99%

PREIMPLANTATION GENETIC TESTING: Single-cell technologies at the forefront of PGT and embryo research

et al. 2020

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While chromosomal mosaicism in the embryo was observed already in the ‘90s using both karyotyping and FISH technologies, the full extent of this phenomenon and the overall awareness of the consequences of chromosomal instability on embryo development has only come with the advent of sophisticated single-cell technologies. High-throughput techniques, such as DNA microarrays and massive parallel sequencing, have shifted single-cell genome research from evaluating a few loci at a time to the ability to perform comprehensive screening of all 24 chromosomes. The development of genome-wide single-cell haplotyping methods have also enabled for simultaneous detection of single-gene disorders and aneuploidy using a single universal protocol. Today, three decades later haplotyping-based embryo testing is performed worldwide to reliably detect virtually any Mendelian hereditary disease with a known cause, including autosomal-recessive, autosomal-dominant and X-linked disorders. At the same time, these single-cell assays have also provided unique insight into the complexity of embryo genome dynamics, by elucidating mechanistic origin, nature and developmental fate of embryonic aneuploidy. Understanding the impact of post-zygotically acquired genomic aberrations on embryo development is essential to determine the still controversial diagnostic value of aneuploidy screening. For that reason, considerable efforts have been put into linking the genetic constitution of the embryo not only to its morphology and implantation potential, but more importantly to its transcriptome using single-cell RNA sequencing. Collectively, these breakthrough technologies have revolutionized single-cell research and clinical practice in assisted reproduction and led to unique discoveries in early embryogenesis.

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Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism

Cited by 145 publications

References 57 publications

Developmental potential of aneuploid human embryos cultured beyond implantation

Developmental potential of aneuploid human embryos cultured beyond implantation

Do human embryos have the ability of self-correction?

PREIMPLANTATION GENETIC TESTING: Single-cell technologies at the forefront of PGT and embryo research

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