Billie Meadowcroft

The basement membrane (BM) is a specialised extracellular matrix tightly tethered to epithelial tissues. While the viscoelastic response of epithelial cells to external deformation has been widely studied, the dynamic mechanical role of its underlying BM remains poorly understood. This is mainly due to its thin, dense, non-fibrillar structure and limited number of model systems that allow live fluorescent imaging of the BM components. Using the Drosophila wing disc, we investigate the BM's response to sustained deformation and find that the tissue retains memory of its shape for up to four hours, enabled by the BM's initial elasticity. However, prolonged deformation leads to BM network rearrangement and loss of mechanical memory, resulting in permanent shape change. Our findings reveal that the BM sets the long-term viscoelastic timescale of epithelial tissues which plays a critical role in maintaining tissue architecture under mechanical stress.

A tutorial review on mesoscale computer simulations of fluid lipid membranes presenting three tutorials with repositories of ready-to-run codes for tether pulling, membrane tubulation and membrane fluctuation analysis.

Collagen IV is one of the main components of the basement membrane, a layer of material that lines the majority of tissues in multicellular organisms. Collagen IV molecules assemble into networks, providing stiffness and elasticity to tissues and informing cell and organ shape, especially during development. In this work, we develop two coarse-grained models for collagen IV molecules that retain biochemical bond specificity and coarse grain at different length scales. Through molecular-dynamics simulations, we test the assembly and mechanics of the resulting networks and measure their response to strain in terms of stress, microscopic alignment, and bond dynamics. Within the basement membrane, collagen IV networks rearrange by molecule turnover, which affects tissue organization and can be linked with enzyme activity. Here we explore network rearrangements via bond remodeling, the process of breaking and remaking of bonds between network molecules. We then investigate the effects of active (enzymatic) bond remodeling. We find that this nonequilibrium remodeling allows a network to keep its integrity under strain, while relaxing fully over a variety of timescales, a dynamic response that is unavailable to networks undergoing equilibrium remodeling.

Collagen IV is one of the main components of the basement membrane, a layer of material that lines the majority of tissues in multicellular organisms. Collagen-IV molecules assemble into networks, providing stiffness and elasticity to tissues and informing cell and organ shape, especially during development. In this work, we develop two coarse grained models for collagen-IV molecules that retain biochemical bond specificity and coarse-grain at different length scales. Through molecular dynamics simulations, we test the assembly and mechanics of the resulting networks and measure their response to strain in terms of stress, microscopic alignment, and bond dynamics. Within the basement membrane, collagen-IV networks rearrange by molecule turnover, which affects tissue organisation and can be linked with enzyme activity. Here we explore network rearrangements via bond remodelling - the process of dynamical breaking and remaking of bonds between network molecules. We then investigate the effects of active (enzymatic) bond remodelling. We find that this non-equilibrium remodelling allows a network to keep its integrity under strain, while relaxing fully over a variety of timescales - a dynamic response that is unavailable to networks undergoing equilibrium remodelling.

Endocytosis is a key cellular process involved in the uptake of nutrients, pathogens, or the therapy of diseases. Most studies have focused on spherical objects, whereas biologically relevant shapes can be highly anisotropic. In this letter, we use an experimental model system based on Giant Unilamellar Vesicles (GUVs) and dumbbell-shaped colloidal particles to mimic and investigate the first stage of the passive endocytic process: engulfment of an anisotropic object by the membrane. Our model has specific ligand-receptor interactions realized by mobile receptors on the vesicles and immobile ligands on the particles. Through a series of experiments, theory, and molecular dynamics simulations, we quantify the wrapping process of anisotropic dumbbells by GUVs and identify distinct stages of the wrapping pathway. We find that the strong curvature variation in the neck of the dumbbell as well as membrane tension are crucial in determining both the speed of wrapping and the final states.

The sequential exchange of filament composition to increase filament curvature was proposed as a mechanism for how some biological polymers deform and cut membranes. The relationship between the filament composition and its mechanical effect is lacking. We develop a kinetic model for the assembly of composite filaments that includes protein–membrane adhesion, filament mechanics and membrane mechanics. We identify the physical conditions for such a membrane remodeling and show this mechanism of sequential polymer assembly lowers the energetic barrier for membrane deformation.

The sequential exchange of filament composition to increase filament curvature was proposed as a mechanism for how ESCRT-III polymers deform and cut membranes. The relationship between the filament composition and its mechanical effect is lacking. We develop a kinetic model for the assembly of composite filaments that includes protein–membrane adhesion, filament mechanics and membrane mechanics. We identify the physical conditions for such a membrane remodelling and show this mechanism is efficient because sequential polymer assembly lowers the energetic barrier for membrane deformation.