Gastruloid-derived primordial germ cell-like cells develop dynamically within integrated tissues.

Primordial germ cells (PGCs) are the early embryonic precursors of gametes - sperm and egg cells. PGC-like cells (PGCLCs) can currently be derived in vitro from pluripotent cells exposed to signalling cocktails and aggregated into large embryonic bodies, but these do not recapitulate the native embryonic environment during PGC formation. Here, we show that mouse gastruloids, a three-dimensional in vitro model of gastrulation, contain a population of gastruloid-derived PGCLCs (Gld-PGCLCs) that resemble early PGCs in vivo. Importantly, the conserved organisation of mouse gastruloids leads to coordinated spatial and temporal localisation of Gld-PGCLCs relative to surrounding somatic cells, even in the absence of specific exogenous PGC-specific signalling or extra-embryonic tissues. In gastruloids, self-organised interactions between cells and tissues, including the endodermal epithelium, enables the specification and subsequent maturation of a pool of Gld-PGCLCs. As such, mouse gastruloids represent a new source of PGCLCs in vitro and, owing to their inherent co-development, serve as a novel model to study the dynamics of PGC development within integrated tissue environments.

Tissue and cell interactions in mammalian PGC development.

Primordial germ cells (PGCs) form early in embryo development and are crucial precursors to functioning gamete cells. Considerable research has focussed on identifying the transcriptional characteristics and signalling pathway requirements that confer PGC specification and development, enabling the derivation of PGC-like cells (PGCLCs) in vitro using specific signalling cocktails. However, full maturation to germ cells still relies on co-culture with supporting cell types, implicating an additional requirement for cellular- and tissue-level regulation. Here, we discuss the experimental evidence that highlights the nature of intercellular interactions between PGCs and neighbouring cell populations during mouse PGC development. We posit that the role that tissue interactions play on PGCs is not limited solely to signalling-based induction but extends to coordination of development by robust regulation of the proportions and position of the cells and tissues within the embryo, which is crucial for functional germ cell maturation. Such tissue co-development provides a dynamic, contextual niche for PGC development. We argue that there is evidence for a clear role for inter-tissue dependence of mouse PGCs, with potential implications for generating mammalian PGCLCs in vitro.