Emerging principles and models of human primordial germ cell development.

In humans, primordial germ cells (hPGCs) are the earliest precursors committed to forming sperm or egg. During the first trimester of embryonic development, hPGCs undergo extensive epigenetic reprogramming and are subject to fitness selection, laying the foundation for future gametogenesis and normal embryonic development. During these processes, hPGCs interact with dynamic microenvironments that remain incompletely understood. Recent advances in transcriptomic and epigenetic profiling have revealed signalling cues and regulatory mechanisms governing hPGC development in human embryos, complemented by insights from non-human primate models. In parallel, pluripotent stem cell-based systems that model hPGC differentiation have emerged in the past decade as valuable platforms for mechanistic studies and form the basis of ongoing efforts to establish human in vitro gametogenesis. In this Review, we discuss the microenvironmental and epigenetic changes accompanying hPGC specification, migration and gonadal development up to week 10 of embryogenesis. Building on these insights, we examine current model systems for recapitulating hPGC development, and highlight the mechanistic understandings they have enabled.