Specification of human germ cell fate with enhanced progression capability supported by hindgut organoids

Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2−3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12−13 and in an E16−17 gastrulating embryo. In vitro, hPGC-like cells (hPGCLCs) can be specified from the intermediary pluripotent stage or peri-gastrulation precursors. Here, we explore the broad spectrum of hPGCLC precursors and how different precursors impact hPGCLC development. We show that resetting precursors can give rise to hPGCLCs (rhPGCLCs) in response to BMP. Strikingly, rhPGCLCs co-cultured with human hindgut organoids progress at a pace reminiscent of in vivo hPGC development, unlike those derived from peri-gastrulation precursors. Moreover, rhPGCLC specification depends on both EOMES and TBXT, not just on EOMES as for peri-gastrulation hPGCLCs. Importantly, our study provides the foundation for developing efficient in vitro models of human gametogenesis. [Display omitted] •Resetting and capacitating precursors are competent for human germ cell fate•Resetting hPGCLCs have an enhanced capability to progress in vitro•Hindgut organoids support hPGCLC progression at a tempo similar to that in vivo•Resetting hPGCLC specification requires both EOMES and TBXT While re-defining the spectrum of germ cell precursors in vitro, Alves-Lopes et al. demonstrate that germ cell-like cells specified from precursors transitioning between primed and naïve pluripotency harbor an enhanced progression capability compared with counterparts derived from peri-gastrulation precursors. Both counterpart precursors may co-exist in the early post-implantation epiblast.