Portrait of Hendrik Marks
Portrait of Hendrik Marks

ZonMW open grant on early human embryogenesis

Hendrik Marks (RIMLS-Science) has received an ZonMW open grant on early human embryogenesis. Together with researchers from Maastricht University/ MUMC+, they will use powerful embryo models to study how human embryos cope with aneuploid cells.

Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is highly prevalent in human embryos derived by in vitro fertilization (IVF). It is a major cause of implantation failure or pregnancy loss, and when persistent can result in offspring with congenital disorders such as Down syndrome.

Exclusion of aneuploid embryos from transfer has thus been the rationale to introduce preimplantation genetic testing for aneuploidy (PGT-A) into IVF clinical practice. However, there is growing evidence that preimplantation embryos of mixed ploidy, so-called mosaic embryos, can result in healthy babies born, suggesting mechanisms within the embryo to rescue aneuploidy and questioning PGT-A efficacy. Hence, the most enigmatic and timely question in clinical embryology is how human embryos regulate genomic fitness: how do aneuploid cells affect developmental and implantation potential of embryos?

Addressing this question is a major challenge, as it requires (i) an accessible model for human blastocyst formation and implantation; (ii) the ability to incorporate (mosaic) aneuploidy within such model; and (iii) compatibility with obtaining spatiotemporal information.

Here, we bring together an ambitious, creative team of researchers with synergistic expertise to meet this challenge. We will test the intriguing hypothesis that aneuploid cells are actively re-positioned and/or eliminated at pre- and peri-implantation stages, dependent on the type and level of the aneuploidy.

The use of “blastoids”, a recently-developed embryo model generated from human pluripotent stem cells, in conjunction with time-lapse imaging and - omics assays that we have pioneered at single cell resolution, allows us to assay lineage commitment and cellular crosstalk during euploid and (mosaic) aneuploid blastocyst formation and implantation. Together, our discoveries will provide new conceptual frameworks regarding plasticity of early human embryos and will add to the decision-making process of clinical embryologists when choosing between embryos of varying aneuploid signatures for transfer to the uterus.

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