Characterization of the human fetal gonad and reproductive tract by single-cell transcriptomics.

During human fetal development, sex differentiation occurs not only in the gonads but also in the adjacent developing reproductive tract. However, while the cellular composition of male and female human fetal gonads is well described, that of the adjacent developing reproductive tract remains poorly characterized. Here, we performed single-cell transcriptomics on male and female human fetal gonads together with the adjacent developing reproductive tract from first and second trimesters, highlighting the morphological and molecular changes during sex differentiation. We validated different cell populations of the developing reproductive tract and gonads and compared the molecular signatures between the first and second trimesters, as well as between sexes, to identify conserved and sex-specific features. Together, our study provides insights into human fetal sex-specific gonadogenesis and development of the reproductive tract beyond the gonads.

Cell-cell interactions during the formation of primordial follicles in humans.

Gametogenesis is a complex and sex-specific multistep process during which the gonadal somatic niche plays an essential regulatory role. One of the most crucial steps during human female gametogenesis is the formation of primordial follicles, the functional unit of the ovary that constitutes the pool of follicles available at birth during the entire reproductive life. However, the relation between human fetal germ cells (hFGCs) and gonadal somatic cells during the formation of the primordial follicles remains largely unexplored. We have discovered that hFGCs can form multinucleated syncytia, some connected via interconnecting intercellular bridges, and that not all nuclei in hFGC-syncytia were synchronous regarding meiotic stage. As hFGCs progressed in development, pre-granulosa cells formed protrusions that seemed to progressively constrict individual hFGCs, perhaps contributing to separate them from the multinucleated syncytia. Our findings highlighted the cell-cell interaction and molecular dynamics between hFGCs and (pre)granulosa cells during the formation of primordial follicles in humans. Knowledge on how the pool of primordial follicle is formed is important to understand human infertility.

Fetal germ cell development in humans, a link with infertility.

Gametes are cells that have the unique ability to give rise to new individuals as well as transmit (epi)genetic information across generations. Generation of functionally competent gametes, oocytes and sperm cells, depends to some extent on several fundamental processes that occur during fetal development. Direct studies on human fetal germ cells remain hindered by ethical considerations and inaccessibility to human fetal material. Therefore, the majority of our current knowledge of germ cell development still comes from an invaluable body of research performed using different mammalian species. During the last decade, our understanding of human fetal germ cells has increased due to the successful use of human pluripotent stem cells to model aspects of human early gametogenesis and advancements on single-cell omics. Together, this has contributed to determine the cell types and associated molecular signatures in the developing human gonads. In this review, we will put in perspective the knowledge obtained from several mammalian models (mouse, monkey, pig). Moreover, we will discuss the main events during human fetal (female) early gametogenesis and how the dysregulation of this highly complex and lengthy process can link to infertility later in life.

Publisher Correction: Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures.

In the version of this Technical Report originally published, the competing interests statement was missing. The authors declare no competing interests; this statement has now been added in all online versions of the Report.

Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures.

Embryonic stem cells can be incorporated into the developing embryo and its germ line, but, when cultured alone, their ability to generate embryonic structures is restricted. They can interact with trophoblast stem cells to generate structures that break symmetry and specify mesoderm, but their development is limited as the epithelial-mesenchymal transition of gastrulation cannot occur. Here, we describe a system that allows assembly of mouse embryonic, trophoblast and extra-embryonic endoderm stem cells into structures that acquire the embryo's architecture with all distinct embryonic and extra-embryonic compartments. Strikingly, such embryo-like structures develop to undertake the epithelial-mesenchymal transition, leading to mesoderm and then definitive endoderm specification. Spatial transcriptomic analyses demonstrate that these morphological transformations are underpinned by gene expression patterns characteristic of gastrulating embryos. This demonstrates the remarkable ability of three stem cell types to self-assemble in vitro into gastrulating embryo-like structures undertaking spatio-temporal events of the gastrulating mammalian embryo.