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.
Impact
The findings of this research will impact assisted reproductive technologies by helping to develop workflows optimized for embryos of both sexes. In the future, the team foresees that the framework they develop will pave the way towards the development of sex-inclusive screening platforms for drugs and other interventions.