The establishment and regulation of human germ cell lineage.

The specification of primordial germ cells (PGCs) during early embryogenesis initiates the development of the germ cell lineage that ensures the perpetuation of genetic and epigenetic information from parents to offspring. Defects in germ cell development may lead to infertility or birth defects. Historically, our understanding of human PGCs (hPGCs) regulation has primarily been derived from studies in mice, given the ethical restrictions and practical limitations of human embryos at the stage of PGC specification. However, recent studies have increasingly highlighted significant mechanistic differences for PGC development in humans and mice. The past decade has witnessed the establishment of human pluripotent stem cell (hPSC)-derived hPGC-like cells (hPGCLCs) as new models for studying hPGC fate specification and differentiation. In this review, we systematically summarize the current hPSC-derived models for hPGCLC induction, and how these studies uncover the regulatory machinery for human germ cell fate specification and differentiation, forming the basis for reconstituting gametogenesis in vitro from hPSCs for clinical applications and disease modeling.