Vrije Universiteit Brussel

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Origin of chromosomal abnormalities in human preimplantation embryos and stem cells

Principal Investigator: Karen Sermon Co-promotors: Inge Liebaers, Claudia Spits, Catherine Staessen, Hilde Van de Velde PhD students: Afroditi Mertzanidou, Kurt Jacobs

Introduction

Human preimplantation embryos are known to carry chromosomal aneuploidies in as much as 40 to 70%, depending on the source of the study. Most of these aneuploidies have been found in embryos that underwent blastomere biopsy, followed by FISH for up to 9 chromosomes, during an IVF cycle with preimplantation genetic screening (PGS). PGS has been applied in IVF patients with a bad prognosis to improve IVF results. Although these aneuploidies are probably the most important factor influencing the potential of the embryo to implant in the uterus, the extent to which aneuploidies play a role is not clear for the following reasons. Firstly, the high number of aneuploidies would predict an even lower rate of implantation after embryo transfer in IVF, and secondly the presence of mosaicism in preimplantation embryos has led researchers to suspect that some of these aneuploidies and mosaicism may self-correct, possibly through selective migration of abnormal cells to the trophectoderm or through apoptosis, during early development of the embryo. These factors most likely explain why PGS has failed to show an effect on IVF pregnancy rates as shown by our own group (Staessen et al., 2004) and others (Twisk et al., 2006). However, not much is known at the cellular level on how these abnormalities arise, how they self-correct, and what their ultimate influence on embryonic development is.

Human embryonic stem cells (hESC) are derived from preimplantation embryos, and hold a great promise in the field of regenerative medicine because of their potential to develop into any cell type of the adult individual. Intensive research over the past 10 years has yielded numerous protocols for the differentiation of hESC into adult cell types. Currently, one of the important issues is the genomic stability of hESC during culture. We (Spits et al., 2008) and others (Baker et al., 2007) have shown that hESC are prone to chromosomal abnormalities, including aneuploidies, fragile site expression and small duplications with a hotspot at 20q21.11. This genomic instability strongly reminds of the behaviour of cancer cells, and is of great concern for the use of hESC for therapeutic purposes or as reliable research models. Nevertheless, little is known about the mechanisms and the influence of the culture conditions on the origin of these abnormalities.

We hypothesize that human embryos and stem cells have a cell cycle that differs from somatic cells in their checkpoints, and that this may be responsible for the proneness of these cells to chromosomal abnormalities.

The aims of this project are:

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