Tissue Mechanics in Growth and Regeneration

As we grow from an embryo to an adult, how do our tissues and organs reach their final correct size and shape? How do they know when to stop growing? The control of normal organ growth is highly complex, but highly important, as when the control system fails, this causes overgrowth, and frequently cancer. When our tissues and organs are damaged by injury, they can often repair themselves in a precisely controlled way to recover their original size and shape. However, this precise repair mechanism also often fails, leading to scarring, fibrosis or tumour like over-growths. Can we understand the regenerative process from a new perspective in order to design new therapies for wound healing and diseases where growth is altered?

These are the questions I would like to answer with my research. Cells can communicate by sending chemical signals to each other. Although chemical control of growth has been widely studied, my novel angle of research is to ask whether physical mechanical forces can influence tissue growth - if you were to stretch or compress tissues, can you alter their growth patterns, change their final size, or improve their regenerative capacity?

There is increasing evidence that a tissue's mechanical environment can have a huge impact on the growth of cells. For example, astronauts in space start to lose their bone mass, because there is no mechanical tension from gravity to stimulate bone formation. Despite the large amount of evidence around us that a tissue's mechanical environment is very important for its growth, surprisingly little work has been done to investigate this at the cell/tissue level. I would like to understand how forces control growth, and eventually apply it to design novel physical treatments for cancer therapy, regenerative medicine, and tissue engineering. This work will require scientists from many backgrounds - biologists, physicists, and engineers - to work together as a team. This interdisciplinary approach will without doubt generate many exciting and creative ideas, and inspire scientists as they learn from each other.

Many biologists have successfully used the wing of the fruit fly as a model to study growth control, revealing many parallels to human growth control. I plan to exploit this model tissue and develop techniques that will allow me to monitor its growth over time, both during its normal development, and after wounding. I also plan to develop a novel technique to stretch and compress this tissue, and then observe what happens to its final size and shape. I hope to put all these data, the pieces of a puzzle, together, into a mathematical/computer model and eventually make a virtual wing. In the model, I'll be able to compare the relative importance of the different control mechanisms, something that's quite hard to do using experiments alone. I will also be able to simulate disease conditions, and treatment strategies, before trying them in real organisms/tissues. I anticipate that this combinatorial approach will greatly increase our efficiency in understanding normal and diseased tissue growth.

The genetic and biochemical control of tissue growth and regeneration has been extensively studied over the last century. However, it is still unclear how the mechanical properties of cells and tissues contribute to how they are formed and sculpted. What is clear is that in order to change the 3D architecture of any structure, there must be forces, acting on the system. Therefore, to fully understand how a tissue reaches its appropriate size, pattern and architecture, we must study its physical characteristics. To this end I aim to address two fundamental questions:

1) How important are the mechanical properties of cells and tissues in generating forces that control patterning, growth and regeneration?
2) Do these forces in turn influence gene expression and signalling pathways?

I will use the Drosophila wing disc, a genetically tractable and easily accessible system, as a model tissue. My approach is to foster a constant interplay between in silico models and in vivo experiments such that hypotheses can be generated and tested more efficiently.

I will measure the mechanical properties of developing and regenerating wing discs, and correlate this with the growth patterns of the wing. I will physically stretch or compress the wing disc using a novel tissue stretcher I have developed, and measure how exogenous forces affect the growth, patterning, and signalling pathways in the wing disc, as well as its regenerative capabilities. This will provide a more causative link between mechanical forces and growth and signalling. Finally, I will build in silico 2D and 3D models to study the sufficiency of mechanical contributions to tissue growth and architectural changes.

Understanding how mechanics can affect tissue growth may eventually lead to novel physical treatment strategies for cancer and tissue regeneration. Implementing the proper mechanical cues in the diseased tissue could induce cellular behaviours that biochemical cues alone could not provide.

The main beneficiaries are likely to be scientists working in related fields (see Academic Beneficiaries). However, this work will also benefit a wider audience:

Training
A large number of undergraduate and graduate students will benefit from their involvement in this interdisciplinary systems level research through summer projects, rotation projects, and MRes programmes. I will be actively involved in PhD programmes such as CoMPLEX at UCL, and hopefully students will gain an understanding and appreciation of the way productive interdisciplinary collaborations work.

Long term clinical impact
Apart from the immediate scientific beneficiaries, my vision is to apply the knowledge gained from this research to design novel physical therapies for tissue repair and regeneration, tissue engineering and cancer treatment. I aim to work with material scientists and engineers to design the optimal tools and biomaterials to improve our treatment of these tissue defects. This has the potential to benefit lifelong national and international human health.

Commercial exploitations
The tissue stretcher that I have developed allows any tissue that can be explanted ex vivo, to be stretched or compressed, and live imaged at the same time - it can be easily modified to fit embryos, neurons, skin grafts, etc. I would like to commercialise this device so that it can be used by a wider range of clinical and non clinical scientists interested in applying forces to their tissue of interest. We have already started to explore patenting options with our collaborators in Paris.

Medical companies
Commercial companies interested in wound healing and anti-scarring/fibrosis therapies could use the mechanical measurement data around wounds to design strategies to counteract the over-growth triggered by the mechanical changes around the wound. Data towards understanding how wounds sense when to stop healing will be critical for medical companies to treat scars and fibrosis.