Potential Mechanism for Self-Correction of Mosaic Embryos

The concept that a mosaic blastocyst with a high percentage of aneuploid cells is less likely to succeed than one with lower percentage of aneuploid cells was extensively demonstrated in a mouse model [45]. experimental data suggests that aneuploid cells, when present at low levels (<50%), could be progressively depleted from the blastocyst stage onward, leading to the development of normal embryos [45] (Figure 9.6). In this regard, using an extended in vitro embryo culture protocol. Papovic et al. investigated the effects of chromosomal aberrations and blastocyst mosaicism on early preimplantation, up to 12 days postfertilization (dpf). They found that human mosaic blastocysts diagnosed with a high percentage of abnormal cells were more likely to be non-viable at 12 dpf. These findings further support the presence of a mechanism for the depletion of abnormal cells in the embryo outgrowths [46].

Several mechanisms have been proposed to explain the “self-correction” process of mosaic embryos. One of these implicates cell death or reduced proliferation of aneuploid cells compared to euploid cells [47]. Direct evidence revealed by studies in mice showed that depletion of aneuploid blastomeres first becomes apparent during blastocyst maturation, when abnormal ICM cells have increased apoptosis and abnormal ТЕ cells exhibit limited proliferation, prior to implantation and later in the early developing embryo [48]. In Bolton’s mouse model, it was shown that the fate of aneuploid cells in early embryos depends on lineage: aneuploid cells in the fetal lineage (i.e., ICM) are eliminated by apoptosis, whereas

Elimination of abnormal cells during blastocyst development

FIGURE 9.6 Elimination of abnormal cells during blastocyst development. Schematic representation of sequential step of chimera (euploid cells in white, aneuploidy cell in blue), representing (a) apoptosis of a aneuploid cells (arrow), followed by engulfment of the apoptotic debris into an efferosome by a neighboring control cell (star): (b) normal cell division of euploid cells (empty arrow) and abnormal cells division of aneuploidy cell (blue arrow).

those in the placental lineage (i.e., ТЕ) showed severe proliferative defects [45] (Figure 9.6). A recent article confirmed that in the human embryo, the dynamics of cell proliferation and death are different, on average, among euploid, mosaic, and aneuploid blastocysts. This could correspond to the proposed selfcorrection mechanism, as aneuploid cells might proliferate more slowly or undergo apoptosis, and euploid cells compensate by elevating their rates of proliferation [46]. Evidence that could support or refute this notion in human embryos, however, is currently lacking. To date, it is unknown whether minimum threshold proportions of euploid cells are required to support normal development.

The self-correction hypothesis is also supported by the notion that the mosaicism rate is less than l%-2% in viable pregnancies [49], which suggests that the phenomenon may also occur during intrauterine development to remove abnormal cells from mammalian embryos in the post-implantation period. The mosaic model used by Bolton et al. [45] was generated with a drug introducing massive chromosome abnormalities for multiple chromosome (complex mosaic) and it remains to be determined if mosaicism for one or few chromosomes results in similar effects on cell survival.

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