Measuring mechanosensation during liver organogenesis

Chronic liver failure is a major global health issue, for which the only treatment currently available is organ transplantation. A promising alternative is the use of cell-based therapies, which aim to replace damaged tissue. However, the regenerative cells of the liver are notoriously difficult to maintain outside of the body as the biochemical signals that they require are poorly understood.
Recent evidence suggests that both biochemical and mechanical cues influence liver stem cell fate during development. Therefore, indicating a role of the cell's mechanical environment (a historically overlooked property) in liver development. This project aims to characterise the differentiation of liver precursor cells in response to mechanical tension. With the ultimate goal of elucidating the influence of mechanical properties on liver development.
The mechanical signalling leading to liver precursor differentiation will be investigated to determine how cells respond to mechanical cues. Biological sensors capable of measuring mechanical stress and key developmental pathways will be deployed for this purpose. This will be executed by incorporating fluorescently labelled proteins into stem cells. The stem cells will then be used to produce liver precursor organoids (mini organs in dishes), therefore replicating organ development outside of the body. The mechanical properties of biomaterials known as hydrogels can then be tailored in order to determine the mechanical prerequisites for the self-organisation of cells during liver development. Therefore, allowing for the deduction of the mechanical requirements for liver growth. Understanding these requirements will hopefully influence the production of future cell therapies capable of treating chronic liver failure. Biophysical techniques, such as optical tweezers, will also be used to measure the cell membrane tension, a property known to be influenced by the mechanical environment, in response to the different hydrogels.
This project is aligned to the EPSRC's research areas: "Biomaterials and tissue engineering", "Biophysics and soft matter physics", "Synthetic biology" and "Sensors and instrumentation".

The primary outputs from the CDT will be cohorts of highly qualified, interdisciplinary postgraduates who are experts in a wide range of sensing activities. They will benefit from a world leading training experience that recognises sensor research as an academic discipline in its own right. The students will be taught in all aspects of Sensor Technologies, ranging from the physical and chemical principles of sensing, to sensor design, data capture and processing, all the way to applications and opportunities for commercialisation, with a strong focus in entrepreneurship, technology translation and responsible leadership. Students will learn in extensive team and cohort engaging activities, and have access to cutting-edge expertise and infrastructure. 90 academics from 15 different departments participate in the programme and more than 40 industrial partners are actively involved in delivering research and business leadership training, offering perspectives for impact and translation and opportunities for internships and secondments. End users associated with the CDT will benefit from the availability of outstanding, highly qualified and motivated PhD students, access to shared infrastructure, and a huge range of academic and industrial contacts.

Immediate beneficiaries of our CDT will be our core industrial consortium partners (MedImmune, Alphasense, Fluidic Analytics, ioLight, NokiaBell, Cambridge Display Technologies, Teraview, Zimmer and Peacock, Panaxium, Silicon Microgravity, etc., see various LoS) who incorporate our cross-leverage funding model into their corporate research strategies. Small companies and start-ups particularly benefit from the flexibility of the partnerships we can offer. We will engage through weekly industry seminars and monthly Sensor Cafés, where SME employees can interact directly with the CDT students and PIs, provide training in topical areas, and, in turn, gain themselves access to CDT infrastructure and training. Ideas can be rapidly tested through industrially focused miniprojects and promising leads developed into funded PhD programmes, for which leveraged funding is available through the CDT.

Government departments and large research initiatives are formally connected to the CDT, including the Department for the Environment, Food and Rural Affairs (DEFRA); the Cambridge Centre for Smart Infrastructure and Construction (CSIC); the Centre for Global Equality (CGE); the National Physics Laboratory (NPL); the British Antarctic Survey (BAS), who all push our CDT to generate impacts that are in the public interest and relevant for a healthy and sustainable future society. With their input, we will tackle projects on assisted living technologies for the ageing population, diagnostics of environmental toxins in the developing world, and sensor technologies that help replace the use of animals in research. Developing countries will benefit through our emphasis on open technologies / open innovation and our exploration of responsible, ethical, and transparent business models. In the UK, our CDT will engage directly with the public sector and national policy makers and regulators (DEFRA, and the National Health Service - NHS) and, with their input, students are trained on impact and technology translation, ethics, and regulatory frameworks.