Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys.

Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys (Macaca fascicularis): cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell‐like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails comprehensive epigenetic reprogramming, including Xi reprogramming, yet Xa and Xi remain epigenetically asymmetric with, as partly observed in vivo, incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi‐reprogramming determinant. We further show that developmental pathway over‐activations with suboptimal up‐regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis. Synopsis: This study establishes a foundation for in vitro oogenesis in cynomolgus monkeys (Macaca fascicularis) by demonstrating the induction of fetal meiotic oocyte‐like cells from embryonic stem cells. Monkey in vitro oogenesis exhibits critical homology with the human system, providing a salient model for advancing human in vitro oogenesis.Induction of fetal meiotic oocyte‐like cells from ESCs in cynomolgus monkeys.Oocyte‐like cell development entails nearly complete DNA methylation reprogramming.X‐chromosome reactivation is partial with remaining epigenetic asymmetries between two X chromosomes.Oocyte‐like cells over‐activate developmental genes with suboptimal meiotic gene expression. [ABSTRACT FROM AUTHOR]