Gastruloids generated without exogenous Wnt activation develop anterior neural tissues

• Published in: Stem cell reports Vol. 16; no. 5; pp. 1143 - 1155
• Main Authors: Girgin, Mehmet U., Broguiere, Nicolas, Mattolini, Lorenzo, Lutolf, Matthias P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.05.2021; Elsevier
• Subjects: Animals; axial patterning; Body Patterning - drug effects; Cell Aggregation - drug effects; Cell Line; embryo development; embryoids; embryonic stem cells; Gastrula - drug effects; Gastrula - growth & development; gastrulation; gastruloids; Germ Layers - cytology; Germ Layers - drug effects; Heterocyclic Compounds, 3-Ring - pharmacology; Hydrogels - pharmacology; Mice; Nerve Tissue - drug effects; Nerve Tissue - growth & development; Organogenesis - drug effects; organoids; Polyethylene Glycols - pharmacology; self-organization; symmetry breaking; trophoblast stem cells; Wnt Proteins - metabolism; Wnt Signaling Pathway - drug effects; embryoids; self-organization; symmetry breaking; embryonic stem cells; gastruloids; organoids; axial patterning; embryo development; trophoblast stem cells; gastrulation
• DOI: 10.1016/j.stemcr.2021.03.017
• ISSN: 2213-6711

When stimulated with a pulse from an exogenous WNT pathway activator, small aggregates of mouse embryonic stem cells (ESCs) can undergo embryo-like axial morphogenesis and patterning along the three major body axes. However, these structures, called gastruloids, currently lack the anterior embryonic regions, such as those belonging to the brain. Here, we describe an approach to generate gastruloids that have a more complete antero-posterior development. We used hydrogel microwell arrays to promote the robust derivation of mouse ESCs into post-implantation epiblast-like (EPI) aggregates in a reproducible and scalable manner. These EPI aggregates break symmetry and axially elongate without external chemical stimulation. Inhibition of WNT signaling in early stages of development leads to the formation of gastruloids with anterior neural tissues. Thus, we provide a new tool to study the development of the mouse after implantation in vitro, especially the formation of anterior neural regions. •Mouse embryonic stem cells can be aggregated to form epiblast-like (EPI) aggregates•EPI aggregates undergo axial morphogenesis in the absence of exogenous WNT activation•Initial aggregate size is a major determinant for axial morphogenesis•Early WNT inhibition is essential for the emergence of anterior neural progenitors In this article, Lutolf and colleagues propose a new method to study post-implantation embryonic development in vitro. Aggregates of mouse embryonic stem cells were shown to differentiate into structures with embryo-like patterning and morphogenesis. Furthermore, initial aggregate size and inhibition of Wnt signaling has been shown to be crucial for the axial morphogenesis and emergence of anterior neural progenitors.