In the last decade, it has become evident that there are critical differences in early embryogenesis between female and male embryos. This is reflected by epidemiologic meta-analyses, showing male-biased embryonic lethality in the first two weeks after conception, followed by a bias towards loss of female embryos. Further evidence is provided by differences in embryo vulnerability and susceptibility, such as after exposure to developmental toxicity or prenatal maternal stress.
While characterization of the sex-specific molecular features is essential to unravel the underlying mechanisms and guide potential interventions, this is notoriously challenging due to the inaccessibility of embryos during pregnancy, and the limited availability and ethical challenges related to the use of surplus IVF embryos. Human pluripotent stem cells (hPSCs), derived from the early embryo, have provided a first glimpse of molecular differences. However, hPSCs lack the spatio-temporal dynamics of embryogenesis, and the complexity of interplay between tissues within the embryo. Therefore, a faithful early embryo-like model to study molecular differences between sexes is urgently needed.
Objective
Recently, the research team has been able to generate human blastoids, an hPSC-derived embryo-like model which faithfully mimics early blastocyst formation, from both female and male hPSCs. Based on these exciting preliminary data, this project aims to further advance the current blastoid embryo-like structures towards an experimental SeXY blastoid system to comprehensively assess sex differences. To meet this challenging aim, Hendrik Marks brings together an ambitious and creative team of researchers with synergistic expertise. SeXY blastoids will test the intriguing hypothesis that the distinct sex chromosomal constitution between female and male embryos affects their epigenetic composition during and after blastocyst formation, impacting blastoid formation and peri- and post-implantation developmental potential.
Design
Within this project, the team will make use of an in-house collection of female and male hPSC lines to induce blastoid formation. This allows to probe for both the variability within sexes and the molecular differences between female and male, using high-resolution single-cell -omics assays that we implemented. To enable pinpointing local changes in cellular activity within the blastoids, the researchers will apply spatial transcriptomics. To gain further functional insight into the molecular mechanisms underlying female and male development, they will study the role of the sex chromosomes. The team will explore the role of dampening of X-linked gene expression in female, which has been suggested to be a critical mechanism for dosage compensation at the blastocyst stage. The induction of aneuploid X0 and XXY hPSCs towards blastoids allows to reveal the relative contribution of the sex chromosome towards blastocyst formation.
