Exploring and Validating the Marmoset as a Primate Model for Chromosomal Instability in Early Development

The presence of aneuploidy (chromosomal abnormalities) in embryos is one of the main barriers to successful human reproduction, causing nearly 50% of early miscarriages. Despite its high incidence in human embryos, our understanding of the molecular mechanisms and cellular developmental fate of aneuploid cells is limited. In this study, we demonstrate that the New World primate marmoset (Callithrix jacchus) is an excellent model for investigating aneuploidy. We developed an efficient method to generate naïve marmoset embryonic stem cells (cj-ESCs) from cj-ESCs in the primed state, resulting in cells that resemble preimplantation epiblast-like cells and possess ground-state pluripotency, allowing them to contribute to all cell lineages, including trophoblasts, and form blastocyst-like structures. We observed that naïve marmoset ESCs are highly chromosomally unstable, making them prone to aneuploidy. We identified inherently less stringent mitotic checkpoints in ground-state embryonic stem cells as a potential cause of chromosomal instability, shedding light on the mechanisms underlying the prevalence of aneuploidy in primates during early embryonic development. Our findings establish that naïve marmoset ESCs faithfully replicate the cellular phenotypes of early embryonic cells, offering a powerful tool for studying the fate of aneuploid cells post-implantation in vivo. Overall design: Bulk RNA-seq data of primed cj-ESCs, euploid Naive cj-ESCs converted and cultured under two different conditions (PLAXA cj-ESCs, PLAXAW cj-ESCs), and 100% aneuploid PLAXAW cj-ESCs. All samples were run with two biological replicates.