2024 Volume 73 Issue 4 Pages 47
The germ-cell lineage ensures the creation of new individuals, perpetuating/diversifying the genetic and epigenetic information across the generations. We have been investigating the mechanism for germ-cell development, and have shown that mouse embryonic stem cells (mESCs)/induced pluripotent stem cells (miPSCs) are induced into primordial germ cell-like cells (mPGCLCs) with a robust capacity both for spermatogenesis and oogenesis and for contributing to offspring. These works have served as a basis for elucidating key mechanisms during germ-cell development such as epigenetic reprogramming, sex determination, meiotic entry, and nucleome programming.
By investigating the development of cynomolgus monkeys as a primate model, we have defined a developmental coordinate of pluripotency among mice, monkeys, and humans, identified the origin of the primate germ-cell lineage in the amnion, and have elucidated the X-chromosome dosage compensation program in primates. Accordingly, we have succeeded in inducing human iPSCs (hiPSCs) into human PGCLCs (hPGCLCs) and elucidated the mechanism of hPGC(LC) specification, demonstrating that the mechanism of germ-cell specification is evolutionarily divergent between mice and humans. Furthermore, we have demonstrated an ex vivo reconstitution of fetal oocyte development in humans and monkeys, and an in vitro induction of meiotic fetal oocytes from monkey ESCs. More recently, we have established a robust strategy for inducing epigenetic reprogramming and differentiation of hPGCLCs into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>1010-fold), creating a foundation for human in vitro gametogenesis.
Here, I would like to provide an overview of these works and discuss our visions for human in vitro gametogenesis research.