Researchers in a 2021 study investigated “self-correction” in a stem cell-based model for mosaic embryos and found that aneuploid cells in a mosaic are more likely to change into trophectoderm cells or die, while euploid cells accumulate in the ICM.
PGS testing (PGT-A) is a technique that allows us to look at the number of chromosomes inside an embryo. The embryo could be euploid, and have the right number of chromosomes (46), or aneuploid with the wrong number of chromosomes. Aneuploid embryos are believed to be a major cause of miscarriage so PGT-A aims to determine which embryos are euploid and therefore have a higher chance of success.
In the past, we believed that embryos were either aneuploid or euploid, meaning that all the cells in the embryo were one or the other. This isn’t the case as we found that some embryos can be a mix of aneuploid and euploid cells, we call these embryos “mosaic” and they’re thought to have an intermediate success rate.
Check my complete guide to mosaic embryos to learn more about mosaics, or my complete guide to PGT-A to get more background on PGT-A (aka PGS testing).
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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The idea is that mosaic embryos can “self-correct” where the aneuploid cells die off or are pushed aside to the trophectoderm, eventually diluting them out of the ICM to the point where it’s more or less euploid.
A new publication in Nature Cell Biology (Yang et al. 2021), have shed some light on this phenomenon in humans.
The researchers created a model for mosaic embryos by using embryonic stem cells. These cells, when placed under special conditions, were able to form “gastruloids” which are more or less lab-grown embryos.
To generate mosaic embryos, they used a chemical that can induce aneuploidy (reversine). By treating some cells with this chemical to make aneuploid cells, and then mixing them with untreated (euploid) cells, they were able to make mosaic embryos to different degrees (containing 25%, 50%, and 75% aneuploid cells).
Next, they added another chemical (BMP4) which forced these embryonic stem cells to differentiate, or change, into either ICM or trophectoderm cells. They did this because they wanted to see what happens to aneuploid cells in a mosaic embryo when they develop – do they die? Stop growing?
They found a couple of things with their mosaic model.
First, aneuploid cells that differentiated into ICM cells were more likely to die compared to trophectoderm cells.
Second, aneuploid cells are more likely to differentiate into trophectoderm cells over ICM cells. When they mixed the cells at different ratios (25-75%), they found more aneuploid cells in the trophectoderm compared to the ICM. This allows the ICM to become enriched in more healthy euploid cells compared to the trophectoderm.
So when aneuploid cells are deciding to differentiate into ICM or trophectoderm cells, they’re more likely to become trophectoderm cells. Trophectoderm cells can tolerate aneuploidy, while cells of the ICM generally do not.
Next, they looked at how real embryos (not their mosaic model!) handle aneuploidy over the course of their development from day 3 onwards. They borrowed data from a couple of other publications that analyzed every cell in an embryo at different times. They found that aneuploidy was highest at day 3 (where over 80% of the individual cells in an embryo were aneuploid) and declined rapidly to about 5% by day 7.
This suggests that aneuploidy may be a normal part of an embryo’s development.
Confined placental mosaicism is a phenomenon where the chromosomal makeup of the placenta doesn’t match the fetus; this occurs in 2% of natural pregnancies and has no adverse impact. The authors suggest that this might be due to aneuploid cells being allocated to the trophectoderm, in order to enrich the euploid cells in the ICM, as shown in this study.
So why is the trophectoderm tolerant of aneuploidy?
Other well-known cells that can tolerate aneuploidy are cancer cells. Cancer cells use aneuploidy to their advantage, as it gives them the ability to grow rapidly and invade other tissues – which in some ways mirrors that of the trophectoderm cells during implantation. It’s possible that aneuploidy in the trophectoderm is tolerated because it’s related to its physiological function.
Although it might be a bit of a stretch to make comparisons between trophectoderm cells and cancer, it does make you wonder!
Overall, this study has shed some light on how aneuploidy is handled in mosaic embryos, and suggests that mosaic embryos might not be as abnormal as some think.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
Related posts:
Complete guide to PGT-A (PGS testing)
Complete guide to mosaic embryos
Ranking 1,000 mosaic embryo transfers
No difference in euploid and mosaic embryo transfers: a clinical trial
PGDIS releases 2021 guidelines for mosaic embryo transfers
A look at how PGT-A results change with age, using data from over 86,000 biopsies
Can a mosaic embryo result in a normal baby?
More sensitive PGT-A test shows that nearly all blastocysts, fetal tissues are mosaic