ESPE Yearbook of Paediatric Endocrinology

In Brief: The authors created mouse embryos in the laboratory from a combination of multiple stem cell lines. These embryos were developed ex vivo up to the equivalent of day 8.5 post-fertilization. Embryos developed within an extraembryonic yolk sac and were similar to whole natural embryos, with defined forebrain and midbrain regions, a beating heart-like structure, a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and also primordial germ cells. Using this model, they showed that ES-C knockout of Pax6 causes ventral domain expansion of the neural tube.

In the same month, another paper by Tarazi et al. (1) from the Weizmann Institute of Science, Israel, reported a similar ‘synthetic’ mouse embryo model containing all embryonic and extraembryonic compartments, and organ progenitors within complex extraembryonic compartments similar to day 8.5 mice embryos.

Comment: These two papers describe major advances in producing embryos ‘in a dish’, past gastrulation (the milestone when the three primary germ layers ectoderm, endoderm and mesoderm are formed), up to roughly mid-gestation (in the mouse). To do this, they generated and cultured together stem cells from all three blastocyst cell types: embryonic stem cells (ES-C), trophoblast stem cells (TS-C), as well as extraembryonic endoderm stem cells (XEN-C). These cells have remarkable innate properties of self-organization, and after 8.5 days they had self-formed ‘embryoids’ that resembled whole natural embryos.

Both groups then showed how these embryoid models can be used as powerful models to understand mechanisms of disease. Amadei et al. studied embryoids formed from Pax6-knockout ES-Cs, to study its impact on early neuronal development. Pax6 is involved in eye and brain development and disruptive mutations cause optic nerve hypoplasia and have been implicated in congenital hypopituitarism. Tarazi et al. modified their embryoids by making their primordial germ cells (PGCs) fluoresce. Remarkably, they could detect PGCs at day 5, specifically at the site of the putative primitive streak. These PGCs then showed ‘normal’ migration to the posterior ventral location by day 8.

More work is needed, in particular to improve the efficiency in generating such embryoids (currently is only around 0.1 to 0.5%). However, these model systems have high potential as disease models to study the impacts of genetic factors on early development as well as to screen chemicals for teratogenic properties.

Reference: 1. Tarazi S, Aguilera-Castrejon A, Joubran C, Ghanem N, Ashouokhi S, Roncato F, Wildschutz E, Haddad M, Oldak B, Gomez-Cesar E, Livnat N, Viukov S, Lokshtanov D, Naveh-Tassa S, Rose M, Hanna S, Raanan C, Brenner O, Kedmi M, Keren-Shaul H, Lapidot T, Maza I, Novershtern N, Hanna JH. Post-gastrulation synthetic embryos generated ex utero from mouse naive ESCs. Cell 2022;185:3290–3306 e25.