Developing quantitative models of tissue morphogenesis using vertex models with boundary constraints

The context of the research

Many human diseases can be traced to defects during embryogenesis. for example, upwards of 50% of human heart disease can be traced to tissues during development. Yet, understanding the fundamental mechanisms driving organ formation remain porrly understood. This is due to lack of accessibility to the organs during their formation.

Recently, organoid systems have been developed, which enable organ-like structures to be grown in the lab from stem cells. These organoids can self-organise into morphologies that resemble the real organs. Using these organoid systems, we cna imagine their formation and use these to develop quantitative models for organ formation.

Until recently, organoids have not been physicallt contstrianed during their growth: yet in vivo, organs do not grow independant from the surrounding space. Here, we plan to explore how boundary constraints and tissue-tissue interactions drive the emergence of complex organ morphology. The aims and objectives of the research

The overarching aim is to develop a three-dimensional model for the initial formation of the human nervous system. Specifically: Aim 1: Advance vertex models to develop three-dimesional cell morphologies with multiple tissue types (year 1) Aim 2: Develop a framework to implement a variety of boundary constraints and tissue-tissue interactions (year 1-3)

Aim 3: Generate quantitative predictions that can be tested in the partner laboratory (year 2-3) The novelty of the research methodology

Vertex models have been extensively used over the past 15-years. However, they have typically been either in two- dimensions or not constrained aggregates in three-dimensions. Yet, in vivo, tissues form layered tissues in three-dimensions within constrained environments.

We will develop novel approaches to tackle more realistic tissue formation that have broad potential for impact. This will provide new insights into the theory of active matter, as well as developing important computational tools that will have broad applicabilty. In particular, the role of boundaries in determining active tissue behaviour is currently poorly understood.

The potential impact, applicaitons and benefits

The study of tissue morphogenesis answers fundamental questions in developmental biology. The development of constrained three-dimensional models of organ fomraiton has wide potential impact and application. At a fundamental level, this framework will enable exploration and testing of active models of living systems, or even deduce which local proliferation and reorganisation patterns are necessary for achieving organ shaping.

The model can also be applied to make specific predictions regarding how complex organ shape emerges. This has potential to provide importnat insights into health and medicine. How the research relates to the remit

EPSRC is fully supportive of interdisciplinary science that applies the strengths of physics and mathematical approaches to biologically relevant problems. This is exemplified by the EPSRC-funded Physics of life grant held between the Saunders, Charras and Briscoe laboratories. The research will generate new models and approaches that will have clear interest to physicists and mathematicians yet will also provide strong insights into fundamental biological questions.

This project falls in Healthcare technologies, Mathematical Sciences and Physical Sciences research areas.

External Partner - Crick Institute - This work is part of a Physics of Life grant awarded to Assoc. Prof Sunders and Dr James Briscoe. James Briscoe and his lab will provide high quality experimental imaging data that is an essential input into the model.

This will involve live movies fo organoids as they form,a s well as imaging data from fixed tissue samples. Importantly, they will also perform perturbation experiments to test model predictions. This back-and-forth is an exciting part of modern quantitative biological approaches.