Mechanical processes underpinning self-organisation in organoids

How do our organs form? While there has been a lot of work in model systems (fly, fish, etc.) to dissect the processes underlying organ formation, it remains challenging to explore this question in humans.

A burgeoning field in biology is that of organoids; organ-like structures grown in a dish from stem cells using specific cocktails of signalling molecules and inhibitors. For example, neural-like tissues can be generated in the lab that resemble the initial formation of the spinal chord in the embryo. Such organoids are accessible for genetic and biophysical analysis.

In this project, we take advantage of neuruloids - an in vitro system that is similar to the process of human posterior neural crest formation. This tissue comprises neural and mesodermal cell types. In work from a collaborating lab (Briscoe lab, Crick), they have shown that such neuruloids can generate complex shapes, such as a doughnut morphology. Further, the mesodermal tissue (which forms the outer ring) can differentiate into distinct regions - the makeup of which depends on the size of the neuruloid.

Here, we ask what are the mechanical processes driving the organoid morphology? While organoids have received substantial genetic analysis, their mechanical state - and how this impacts morphogenesis - remains poorly characterised. Working with our collaborator lab (Charras, UCL), we will utilise a range of biophysical approaches to dissect the organoid mechanics. This includes atomic force microscopy, traction force microscopy, Bayesian force inference and detailed analysis of the distribution of key mechanical proteins such as actin and myosin. This mechanical information will be integrated within a computational model to deepen our understanding of how complex tissue morphology can emerge in a self-organised manner.

This project has clear potential for impact on human health. Numerous human diseases are related to developmental defects. Yet, we know little about how our organs form at a cellular level. Here, we will provide new insights into how mechanical differences between cell types drive human organ development.