Abstract

Human germline cells are crucial for maintenance of the species. However, the developmental trajectories and heterogeneity of human germline cells remain largely unknown. We performed single-cell RNA -seq and DNA methylome sequencing analysis of human germline cells in female and male human embryos spanning several critical developmental stages. We found that female fetal germ cells (FGCs) undergo four distinct sequential phases characterized by mitosis, retinoic acid signaling, meiotic prophase, and oogenesis. Male FGCs develop through stages of migration, mitosis, and cell-cycle arrest. Individual embryos of both sexes simultaneously contain several subpopulations, highlighting the asynchronous and heterogeneous nature of FGC development. Moreover, we observed reciprocal signaling interactions between FGCs and their gonadal niche cells, including activation of the bone morphogenic protein (BMP) and Notch signaling pathways. Our work provides key insights into the crucial features of human germline cells during their highly ordered mitotic, meiotic, and gametogenetic processes in vivo.