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Studying cell fate, axial patterning & morphogenesis with Gastruloids

Left-Right Asymmetry

The exterior of all vertebrates is bilaterally symmetric, but their interior is highly asymmetrical in both the positioning and the anatomy of internal organs such as the heart, viscera, lungs, gut and brain. The patterning process that leads to this left-right (LR) asymmetry is highly conserved, with the same positional bias in structures such as the heart and visceral organs observed from amphibians to birds and mammals. In humans, failure to correctly specify the asymmetrical placement (situs) and orientation of the different organs leads to a number of pathologies and severe birth defects such as heterotaxia, situs inversus, right/left isomerism, and congenital heart defects. Therefore, in addition to its central biological importance, understanding the origin and regulation of asymmetric patterning has clear biomedical implications.

Despite a vast number of studies into the regulation of LR patterning, the precise mechanisms generating this asymmetry are still subject to debate. Furthermore, the only current methods available to study these events involve the use of forward or reverse genetics in animal models. Although these have been used to great effect, they are difficult to manipulate, expensive and require large numbers of animals to ensure proper statistical power.

We are taking an alternative approach to study the mechanisms of LR asymmetry by using a novel technique called Gasturloids. Gastruloids ('Embryonic Organoids) are 3D aggregates of mouse embryonic stem cells (mESCs) that, over time, develop axial organisation and display gastrulation-like movements that mimic events in embryos. Gastruloids generate all embryonic axes (anteroposterior, dorsoventral, mediolateral), and develop bilateral asymmetry, similar to LR-asymmetry. This patterning is associated with a Node-like structure that is dependent on Nodal signalling, as in the embryo. 

This opens up a unique experimental system to study the molecular mechanisms associated with the emergence of LR asymmetry in the mammalian embryo as well as a system for the study of genes and disease states. Such an experimental system allows experiments to be performed which are otherwise difficult to accomplish in embryos and since it is a tissue-culture based assay, it has the added benefit of replacing, reducing and refining the requirement for animal-based studies.

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