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The germ cell lineage gives rise to totipotency and perpetuates and diversifies genetic as well as epigenetic information. Specifically, germ cells undergo epigenetic reprogramming/programming, replicate genetic information with high fidelity, and create genetic diversity through meiotic recombination. Driven by advances in our understanding of the mechanisms underlying germ cell development and stem cell/reproductive technologies, research over the past 2 decades has culminated in the in vitro reconstitution of mammalian germ cell development: mouse pluripotent stem cells (PSCs) can now be induced into primordial germ cell-like cells (PGCLCs) and then differentiated into fully functional oocytes and spermatogonia, and human PSCs can be induced into PGCLCs and into early oocytes and prospermatogonia with epigenetic reprogramming. Here, I provide my perspective on the key investigations that have led to the in vitro reconstitution of mammalian germ cell development, which will be instrumental in exploring salient themes in germ cell biology and, with further refinements/extensions, in developing innovative medical applications.

The development of an in vitro system in which human primordial germ cell-like cells (hPGCLCs) are generated from human pluripotent stem cells (hPSCs) has been invaluable to further our understanding of human primordial germ cell (hPGC) specification. However, the means to evaluate the next fundamental steps in germ cell development have not been well established. In this study we describe a two dimensional extended culture system that promotes proliferation of specified hPGCLCs, without reversion to a pluripotent state. We demonstrate that hPGCLCs in extended culture undergo partial epigenetic reprogramming, mirroring events described in hPGCs in vivo, including a genome-wide reduction in DNA methylation and maintenance of depleted H3K9me2. This extended culture system provides a new approach for expanding the number of hPGCLCs for downstream technologies, including transplantation, molecular screening, or possibly the differentiation of hPGCLCs into gametes by in vitro gametogenesis.

The development of an in vitro system in which human primordial germ cell-like cells (hPGCLCs) are generated from human pluripotent stem cells (hPSCs) has been invaluable to further our understanding of human primordial germ cell (hPGC) specification. However, the means to evaluate the next fundamental steps in germ cell development have not been well established. In this study we describe a two dimensional extended culture system that promotes proliferation of specified hPGCLCs, without reversion to a pluripotent state. We demonstrate that hPGCLCs in extended culture undergo partial epigenetic reprogramming, mirroring events described in hPGCs in vivo, including a genome-wide reduction in DNA methylation and maintenance of depleted H3K9me2. This extended culture system provides a new approach for expanding the number of hPGCLCs for downstream technologies, including transplantation, molecular screening, or possibly the differentiation of hPGCLCs into gametes by in vitro gametogenesis.