Unifying synthetic embryology

Abstract

During embryonic development, a fertilized egg transitions into a complex organism, whereby diverse cell types are spatially organized into functional tissues. This sequential unfurling of complexity is exemplified perhaps best at gastrulation, where the major axes of the adult are laid down and the principal germ layers are defined in tandem with a dramatic change in morphology (Tam and Behringer, 1997; Arnold and Robertson, 2009). Understanding the mechanisms by which this highly choreographed process plays out demands investigation at different spatial scales (Shahbazi et al., 2019): from the cell-intrinsic gene-regulatory networks that govern cell fate decisions; to the signaling interactions that coordinate divergent fate trajectories across tissues. It requires understanding of how these regulatory processes are coupled to global characteristics including embryonic geometry, patterning, and inter-tissue interactions. Dissecting mechanisms across such scales — and crucially understanding their interactions — requires the capacity to manipulate genes, signals and morphology, a task that has proved challenging particularly for mammalian experimental embryology given the inaccessibility of the conceptus at implantation, a time when many of these important events occur (Hadjantonakis et al., 2020; Shahbazi and Zernicka-Goetz, 2018). Synthetic embryology has risen to this challenge, engineering embryo-like structures — "stembryos" — using stem cells derived from embryos situating cells in both near-native and more foreign contexts, and probing the consequences for patterning and morphogenesis. Given the recent explosion of diversity in stembryo models (Harrison et al., 2017; Rivron et al., 2018; Shao et al., 2017a; Sozen et al., 2018; Van den Brink et al., 2014; Veenvliet et al., 2020; Warmflash et al., 2014; Amadei et al., 2020), this Special Issue reflects on the successes made and the challenges that remain in using in vitro culture platforms to study early mammalian embryogenesis. Here, we offer a perspective on the purpose and utility of synthetic embryology, proposing that focusing efforts on probing fundamental mechanisms of self-organization, spurred via novel bioengineering strategies, can help unify the field towards its shared motivations of understanding natural development and building reliable, translatable experimental models.

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