Unravelling the biophysical mechanisms that regulate liver fibrosis

"Unravelling the Biophysical Mechanisms That Regulate Liver Fibrosis

Project Summary:

Research Context:

Many human diseases are driven or worsened by pathological matrix remodelling, a process that disrupts the structure and function of the extracellular matrix (ECM). This is particularly evident in chronic liver diseases (CLDs), such as metabolic dysfunction-associated steatohepatitis (MASH, formerly known as non-alcoholic steatohepatitis or NASH), which results in tissue fibrosis and impaired liver function.

Recent studies have demonstrated that a decellularised human liver matrix, combined with high-content imaging, a technique designed to maximise data capture, can investigate matrix remodelling in simplified tissue models. However, a significant limitation is the lack of in vitro tools capable of effectively visualising, quantifying, and manipulating pathological matrix remodelling to better understand its role in disease progression.

Aims:

This project aims to develop a cutting-edge toolkit for investigating matrix remodelling in an in vitro model of liver fibrosis. The toolkit will integrate hydrogels with adjustable mechanical properties, high-content imaging to capture cell-driven alterations in stiffness, rheological techniques to monitor localised hydrogel degradation in real-time, and fluorescence-based sensors for detecting matrix breakdown. This approach provides a robust platform for visualising and quantifying matrix dynamics in liver disease models. The toolkit will be validated by examining how matrix remodelling shapes cellular behaviour within our human liver model, with a particular focus on its role in regulating the production and degradation of proteins involved in fibrosis.

Objectives:

To achieve this, there will be three main objectives: first, developing an in vitro fibrosis model to map extracellular matrix (ECM) remodelling using advanced imaging techniques; second, designing hydrogels that replicate the dynamic mechanical properties observed in fibrotic human liver tissues; and third, validating the effectiveness of the toolkit in an in vitro model to investigate matrix degradation."