Tissue Mechanics in Growth and Regeneration

Lead Research Organisation: University College London
Department Name: MRC Laboratory of Molecular Cell Biology

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description EMBO Young Investigator Programme
Amount € 15,000 (EUR)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 01/2019 
End 01/2023
 
Description International Young Scientist Fellowship
Amount ¥200,000 (CNY)
Organisation National Natural Science Foundation of China 
Sector Public
Country China
Start 01/2017 
End 12/2017
 
Description L'oreal UNESCO Women in Science Fellowship
Amount £15,000 (GBP)
Organisation L'Oreal (Paris) 
Sector Private
Country France
Start 07/2018 
End 07/2019
 
Description Lister Institute Research Prize Fellowship
Amount £250,000 (GBP)
Organisation Lister Institute of Preventive Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2023
 
Description MRC Strategic Skills Fellowship
Amount £316,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2016 
End 04/2019
 
Description Marie Sklodowska-Curie Fellowship
Amount € 190,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2016 
End 01/2018
 
Description Marie Sklodowska-Curie ITN Grant
Amount € 247,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2015 
End 09/2019
 
Description Sir Henry Wellcome Fellowship
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2014 
End 02/2018
 
Title EpiTools: a new open source image analysis platform 
Description A new modular software that allows automatic segmentation and tracking of time lapse images for epithelial tissue development. 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact Quantitative data /image analysis has been made possible, saving potentially thousands of hours of human work time. Still to be published and publicly available. 
 
Title Tissue stretcher and compressor 
Description A novel method / research tool / device that allows the stretching or compressing of tissues during in vitro culturing 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Has allowed the assessment of the impact of direct physical force on developing tissues, which was not possible before. Novel findings yet to be consolidated and published. 
 
Title EpiTools: a new open source image analysis platform 
Description A modular image analysis pipeline that allows automatic segmentation and tracking of live imaging data for epithelial tissues 
Type Of Material Data analysis technique 
Year Produced 2014 
Provided To Others? Yes  
Impact Has allowed high throughput data analysis of time lapse data. 
 
Description Building a finite element model of Drosophila wing disc growth 
Organisation Polytechnic University of Catalonia
Country Spain 
Sector Academic/University 
PI Contribution Most of the work is performed by a postdoc in my lab. All computational resources.
Collaborator Contribution Our collaborator has hosted my postdoc in his group for 2 months last summer, and provides regular advice/feedback on her work
Impact Sir Henry Wellcome Fellowship has been awarded to Melda Tozluoglu (postdoc working on the project). Multidisciplinary: developmental biology, biomechanics, computational modelling
Start Year 2014
 
Description Cell division orientations upon stretch 
Organisation University College London
Department MRC Laboratory for Molecular Cell Biology (LMCB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Performed stretching of wing disc experiments to see effect on cell division and spindle orientation
Collaborator Contribution Performed experiments in notum
Impact Paper in preparation
Start Year 2017
 
Description CellFit - inferring forces in wing discs from live imaging data 
Organisation Rensselaer Polytechnic Institute
Department Civil and Environmental Engineering
Country United States 
Sector Academic/University 
PI Contribution All experimental data, fly lines, microscopy equipment
Collaborator Contribution Developers of the CellFit software - helping us validate and improve the software for our uses
Impact Fellowship for Rob Tetley (postdoc in my lab working on the project). Multidisciplinary: genetics, imaging, mechanics
Start Year 2014
 
Description Computational modelling of the fly retina epithelium 
Organisation University College London
Department MRC Laboratory for Molecular Cell Biology (LMCB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Using a vertex model to simulate and unravel the physical mechanisms behind retinal cell morphogenesis
Collaborator Contribution All experimental data acquisition.
Impact Paper being written. Multidiscipline: Genetics, computational modeling, biophysics, developmental biology
Start Year 2015
 
Description EpiTools: a new open source image analysis platform 
Organisation Kingston University London
Country United Kingdom 
Sector Academic/University 
PI Contribution Created the original concept/problem, provided experimental data, started developing the image analysis software.
Collaborator Contribution Provided further technical input into developing the software and creating a user friendly platform
Impact Paper published in Dev Cell 2016. An open source software will be available. Multiple disciplines: developmental biology, imaging, image analysis, computer vision
Start Year 2011
 
Description EpiTools: a new open source image analysis platform 
Organisation University of Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution Created the original concept/problem, provided experimental data, started developing the image analysis software.
Collaborator Contribution Provided further technical input into developing the software and creating a user friendly platform
Impact Paper published in Dev Cell 2016. An open source software will be available. Multiple disciplines: developmental biology, imaging, image analysis, computer vision
Start Year 2011
 
Description Mass Spec 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Concept and experimental design, providing tissue samples
Collaborator Contribution Mass spec expertise
Impact none yet
Start Year 2018
 
Description Measuring mechanical properties of wing discs with U shaped stretcher devices 
Organisation University College London
Department London Centre for Nanotechnology
Country United Kingdom 
Sector Academic/University 
PI Contribution Fly strains and Drosophila expertise
Collaborator Contribution Stretcher device
Impact Marie Curie Fellowship for Maria Duda (postdoc working on the project). Multidisciplinary: genetics, cell biology, biophysics
Start Year 2014
 
Description Measuring mechanical properties of wing discs with micropipette techniques 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Initial concept development, tissue culture techniques
Collaborator Contribution Micropipetting techniques to measure mechanical properties
Impact In progress.
Start Year 2014
 
Description Mechanical modelling of mitotic cell shape changes 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Building a mechanical model of mitotic cell shape changes in an epithelium and providing experimental data in the wing disc tissue
Collaborator Contribution Providing experimental data from notum tissue and cell culture
Impact In progress. Multiple disciplines: biophysics, computational mechanics, imaging, developmental biology, cell biology
Start Year 2014
 
Description Mechanical modelling of wing disc wound healing 
Organisation Polytechnic University of Catalonia
Country Spain 
Sector Academic/University 
PI Contribution All experimental data, Drosophila strains, imaging and lab equipment
Collaborator Contribution The building and testing of a new mechanical computational model of epithelium
Impact Multidisciplinary: cell biology, quantitative imaging, image analysis software development, biomechanics, computational modelling
Start Year 2016
 
Description Mechanisms of actomyosin force regulation during epithelial tissue patterning 
Organisation University College London
Department MRC Laboratory for Molecular Cell Biology (LMCB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Performed vertex model simulations of drosophila pupal retinal development
Collaborator Contribution Carried out experiments
Impact Manuscript in preparation
Start Year 2017
 
Description Modelling viral spread 
Organisation University College London
Department MRC Laboratory for Molecular Cell Biology (LMCB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Building a new computational model of viral spread in cells
Collaborator Contribution All experimental work
Impact Paper being prepared. Multidiscipline: virology, cell biology, computational modelling
Start Year 2016
 
Description Organoid Cellesce 
Organisation Cellesce Ltd
PI Contribution Experimental design and concept development
Collaborator Contribution Organoid culture expertise
Impact none yet
Start Year 2018
 
Description Organoids 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Concept and experimental design
Collaborator Contribution Organoid culture expertise
Impact none yet
Start Year 2018
 
Description Regeneration in Drosophila wing discs using Gal80/Gal4/UASrpr system 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution We have been performing most of the experiments, including mostly fixed confocal imaging and live imaging.
Collaborator Contribution They have provided some essential Drosophila fly strains
Impact An MRC Strategic Skills Fellowship has been awarded to Rob Tetley (postdoc in my lab working on this project). Multidisciplinary: genetics, biophysics, quantitative image analysis software development
Start Year 2014
 
Description TaDa technique 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Concept and experimental design and tissue samples
Collaborator Contribution TaDa technique
Impact none yet
Start Year 2017
 
Description Tissue Stretcher - effect of exogenous force on tissue growth and morphogenesis 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution We created the concept of making a versatile tissue stretcher and compressor device and designed the novel system and device.
Collaborator Contribution My partners have assisted with PDMS micro patterning techniques and the making of a prototype of a first version of the tissue stretcher. They are also helping with making force measurements on the wing disc tissue.
Impact A publication for this new technique is currently being prepared, and we are also seeking patenting options. Multiple disciplines for this research: biophysics, nanotechnology, cell biology, developmental biology
Start Year 2011
 
Description Tissue Stretcher - effect of exogenous force on tissue growth and morphogenesis 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We created the concept of making a versatile tissue stretcher and compressor device and designed the novel system and device.
Collaborator Contribution My partners have assisted with PDMS micro patterning techniques and the making of a prototype of a first version of the tissue stretcher. They are also helping with making force measurements on the wing disc tissue.
Impact A publication for this new technique is currently being prepared, and we are also seeking patenting options. Multiple disciplines for this research: biophysics, nanotechnology, cell biology, developmental biology
Start Year 2011
 
Description Vertex modelling of wound healing 
Organisation University College London
Department Department of Physics & Astronomy
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing experimental data for epithelia wound healing
Collaborator Contribution Performed simulations with a vertex model to test how tissue dynamics affect wound healing
Impact Paper in preparation. Multidiscipline - biology, physics, computational modelling
Start Year 2017
 
Description Voronoi: Fundamental physical constraints drive cellular self-organization of tissues 
Organisation University of Seville
Country Spain 
Sector Academic/University 
PI Contribution Performed computational simulations, using vertex model, to understand different physical forces on epithelial patterning
Collaborator Contribution Performed Voronoi tesselations, data analysis.
Impact Paper published in EMBO Journal 2016
Start Year 2014
 
Title EpiTools 
Description This is an image analysis toolkit. It allows for automated segmentation and tracking of live imagining data of epithelia. Cellular morphometrics can be extracted quantitatively. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact Many researchers have downloaded and started to use this software for their analysis 
URL http://tiny.uzh.ch/dm
 
Description BBC Radio Manchester interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview with BBC Radio Manchester regarding my Loreal UNESCO Women In Science award. Discussed my research and outreach activities on the programme.
Year(s) Of Engagement Activity 2018
 
Description Cambridge AWiSE Career Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Career advice for women in science, organised by Cambridge AWiSE and MRC LMB. I was among 3 invited speakers. Gave a talk, followed by Q&A discussions.
Year(s) Of Engagement Activity 2018
URL https://camawise.org.uk/2018/06/15/camawise-and-mrc-lmb-career-lunch-2018/
 
Description China Bridge UK Summer Camp LMCB science tour 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact 15 students from China aged between 11-16 attended a school visit at the LMCB. They were introduced to the work done at the institute, and had the hands on opportunity to try 3 lab activities. This increased their interest in Biology and many have said this was the best part of their 2 week summer camp in London. Some have said this has inspired them to apply to UK universities in the future. This is now an annual event.
Year(s) Of Engagement Activity 2016,2017
 
Description PandaRadio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview with PandaRADIO regarding my Loreal UNESCO Women In Science award. Discussed my research and outreach activities on the programme.
Year(s) Of Engagement Activity 2018
 
Description School Visit (North London Collegiate) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I gave a talk about my research to the school's STEM club. Received very positive feedback afterwards.
Year(s) Of Engagement Activity 2018
 
Description TalkRADIO interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview with TalkRADIO regarding my Loreal UNESCO Women In Science award. Discussed my research and outreach activities on the programme.
Year(s) Of Engagement Activity 2018
 
Description Visited a school to talk about my research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Gave a talk at a girl's school to promote more STEM interest and future studies. I talked about my interdisciplinary research and career path. Feedback from students, including articles in their school magazine, were excellent. Many said they are considering science at university, and found it fascinating that physics and computer modelling had such a role in biology.
Year(s) Of Engagement Activity 2017
 
Description eLIFE interview - Parent Scientist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Participated in a interview for eLife journal regarding challenges as a parent scientist.
Year(s) Of Engagement Activity 2018
URL https://elifesciences.org/interviews/2b2812a7/yanlan-mao