How geometry drives patterning in organoids

Organoids have shown immense potential in mimicking human organs and development. Self-organisation of the stem cells is one of the critical processes underlying the organoid development. However, the lack of control in this event also gives rise to issues concerning reproducibility of the organoid cultures. This factor limits its broader adoption in academia and industry. In a recent study published in Science, the researchers used geometry and physical cues to control the patterning and morphogenesis of organoids. 

The functional structures of organs often result from complex interplay between the self-organisation and microenvironmental cues. To understand this crosstalk the researchers controlled the initial geometry of the microenvironment via photopatterning of the hydrogels on which the organoids are grown. This was done using specialised hydrogels that undergo degradation and softening when exposed to specific wavelength of light. Using localised light, they were able to induce softening at specific regions, and thus modify the stiffness of that region. The cells that were adjacent to the regions with drop in stiffness underwent evagination and formed buds. These structures were completely absent in regions that did not experience change in stiffness. 

Thus, using these physical cues in the extracellular matrix, the authors were able to build organoids of controlled shape and size. They could also show that heterogeneities in the physical cues were driving this process via YAP (Yes-associated protein) signalling. Heterogeneities in the activity of YAP, a transcriptional regulator, could lead to suppression of stem cell fates in certain regions and triggering the differentiation process. 

The authors add that changes in tissue geometry or morphology can lead to symmetry breaking events, which in turn lead to a cascade of signalling driving the spatial organisation of organoids. Thus, mechanics of the extracellular matrix and hydrogels can be used to standardise the size and shape of organoids, reduce variabilities in the self-organisation process, and dictate their course of development. These factors, in turn, could lead to broader adoption and use of these methods across labs and settings.