A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization

Abstract

Summary The earliest aspects of human embryogenesis remain mysterious. To model patterning events in the human embryo we used colonies of human embryonic stem cells (hESCs) grown on micropatterned substrate and differentiated with BMP4. These gastruloids recapitulate the embryonic arrangement of the mammalian germ layers and provide an assay to assess the structural and signaling mechanisms patterning the human gastrula. Structurally, high-density hESCs lateralize their TGF-β receptors to their lateral side in the center of the colony, while maintaining apical localization of receptors at the edge. This relocalization insulates cells at the center from apically applied ligands while maintaining response to basally presented ones. Additionally, BMP4 directly induces the expression of its own inhibitor, Noggin, generating a reaction-diffusion mechanism that underlies patterning. We develop a quantitative model that integrates edge sensing and inhibitors, to predict human fate positioning in gastruloids, and potentially the human embryo.

Embryoids, organoids and gastruloids: new approaches to understanding embryogenesis

“…Instead, with the decreased tissue size they lose the fates that are normally present at the colony interior, as would be expected for a signaling mechanism that is restricted to the edge (Fig. 2E) (Etoc et al, 2016). It is currently unclear whether organoids and embryoids exhibit any growth or pattern scaling control.…”

“…We consider the term embryoid to represent a more organized embryoid body that arises as a consequence, for instance, of cell polarization induced by the ECM in the surrounding medium or due to the correct topology of multiple cell types representing an embryo at a certain time of development. Gastruloids, by contrast, are models of a gastrulating embryo, either in 2D (Etoc et al, 2016;Warmflash et al, 2014) or in 3D (Turner et al, 2016;van den Brink et al, 2014). Self-assembly/ organization has also been observed directly in attached mammalian blastocysts in vitro.…”

“…As BMP4 produces its own inhibitor, noggin, a morphogen gradient is formed from the edges inward, causing radial patterning (Fig. 2E) (Etoc et al, 2016).…”

Creating to understand – developmental biology meets engineering in Paris

“…He focused on simulations of the gene regulatory rules governing early pluripotent stem cell commitment (Onishi et al, 2014), as well as on the interplay between chemical and physical factors in the establishment of patterns in vitro (Peerani et al, 2007), including those recently described by Warmflash et al (Etoc et al, 2016;Warmflash et al, 2014). Crucially, Zandstra outlined the ambitious and challenging questions that lie ahead.…”

Human embryo research and the 14-day rule

“…Recent studies have described the successful growth of human embryos to a chronological and developmental stage approaching this limit (Deglincerti et al, 2016;Shahbazi et al, 2016), and other work has reported the generation of embryo-like structures from mouse and human pluripotent stem cells that mimic the gastrulating embryo in form and cellular content (Etoc et al, 2016;Harrison et al, 2017;Shao et al, 2017;van den Brink et al, 2014). These advances have prompted a re-examination of the current restrictions on human embryo culture (Hyun et al, 2016).…”