Using Embryo Models to Understand the Development and Progression of Embryonic Lineages: A Focus on Primordial Germ Cell Development

Abstract

Background: Recapitulating mammalian cell type differentiation in vitro promises to improve our understanding of how these processes happen in vivo, while bringing additional prospects for biomedical applications. The establishment of stem cell-derived embryo models and embryonic organoids, which have experienced explosive growth over the last few years, opens new avenues for research due to their scale, reproducibility, and accessibility. Embryo models mimic various developmental stages, exhibit different degrees of complexity, and can be established across species. Since embryo models exhibit multiple lineages organized spatially and temporally, they are likely to provide cellular niches that, to some degree, recapitulate the embryonic setting and enable "co-development" between cell types and neighbouring populations. One example where this is already apparent is in the case of primordial germ cell-like cells (PGCLCs).

Summary: While directed differentiation protocols enable the efficient generation of high PGCLC numbers, embryo models provide an attractive alternative as they enable the study of interactions of PGCLCs with neighbouring cells, alongside the regulatory molecular and biophysical mechanisms of PGC competency. Additionally, some embryo models can recapitulate post-specification stages of PGC development (including migration or gametogenesis), mimicking the inductive signals pushing PGCLCs to mature and differentiate and enabling the study of PGCLC development across stages. Therefore, in vitro models may allow us to address questions of cell type differentiation, and PGC development specifically, that have hitherto been out of reach with existing systems.

Key message: This review evaluates the current advances in stem cell-based embryo models, with a focus on their potential to model cell type-specific differentiation in general and in particular to address open questions in PGC development and gametogenesis.

Keywords: Embryo models; Embryonic organoids; Primordial germ cells; Stem cell-derived embryo models.

Fig. 1

Schematic representation of human and mouse primordial germ cell development (PGC) in vivo (upper half of figure) with selected embryo models and embryonic organoids (lower half of figure; human drawings partially adapted from [114]). The different in vitro models are positioned with respect to their resembling features along the in vivo developmental timeline. Note that this is a tentative placement according to particular features of the in vitro systems as they are currently, and may not reflect the potential of each model in the future. Embryo models have been categorized according to their potential to address questions in primordial germ cell specification (blue), migration and epigenetic reprogramming (green), and gametogenesis (orange). Mm, Mus musculus (Mouse); Mf, Macaca fascicularis (Macaque); Hs, Homo sapiens (Human).

Fig. 2

Graphical representation of selected embryo models that show potential to understand competency for primordial germ cell (PGC) specification, and early post-specification stages. The figure includes 2D micropattened colonies, posteriorized embryonic-like sacs, gastruloids, embryonic–trophoblast–extra-embryonic endoderm (ETX-) embryoids, perigastruloids, and SEMs (Stem-cell-based embryo models), schematically representing the different tissues relevant in primordial germ cell development. Mm, Mus musculus (Mouse); Hs, Homo sapiens (Human).

Fig. 3

Graphical representation of selected embryo models and embryonic organoids to study primordial germ cell (PGC) post-specification stages, including migration and epigenetic reprogramming. The figure includes human hind gut organoids and mouse gastruloids, including also their initial and final stages before and after maturing in vitro. Mm, Mus musculus (Mouse); Hs, Homo sapiens (Human).

Fig. 4

Selected embryo models recapitulating aspects of the entry and progression of primordial germ cell-like cells to gametogenesis. The figure contains a schematic representation of xenogenic reconstituted ovaries, reconstituted testis, and reconstituted ovarioids. Mm, Mus musculus (Mouse); Hs, Homo sapiens (Human); rOvaries, reconstituted ovaries; xrOvaries, xenogeneic reconstituted ovaries; rTestes, reconstituted testes.