Role of active membrane fluctuations in the regulation of biological functions

• Applicant: Professorin Dr. Ana-Suncana Smith
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545889871

For decades, the biophysical community has been investigating cell membrane fluctuations around a constantly evolving shape with amplitudes of up to several hundred nanometers. It is now clear that they comprise a thermal and an active component that vary with the overall state of the cell in a spatially dependent manner. While the state of the cell and its regulation changes depending on the physiological function of the cell, in our recent work we have found an intriguing commonality between different cell types - from red blood cells to macrophages, all cells exhibit a fluctuation spectrum with identical characteristics. However, unlike the well-established link between cell shape and biological function, the physiological significance of membrane fluctuations is still debated. One of the problems in resolving this debate is the lack of a minimal mimetic system in which the spectrum of active cell fluctuations can be reconstituted, manipulated and studied in the context of a particular process relevant to cell function. This is the problem that we aim to address in this project, building on the French team's experience in constructing active cell mimetic systems and the German team's expertise in modelling them. Specifically, we will assemble cell-sized vesicles encapsulating a cell extract, which we will supplement with cytoskeletal elements to induce and tune the dynamics of active forces. We will quantify the resulting active membrane fluctuations using our unique repertoire of advanced optical microscopy techniques. We will compare the mimetic system with independent cellular measurements in selected cell types. We will analyze our measurements using our recently developed active membrane framework. Once the mimetic system is established, we will combine in-vitro experiments and theory to be elaborated here, to unveil to what extent active membrane fluctuations regulate compositional membrane organization using phase separating lipids/cholesterol mixtures. This will provide a deeper insight into the coupling of the fast dynamics induced by the cytoskeleton in (mimetic) cell shape fluctuations and the membrane organization, which has so far only been studied with a static coupling. Finally, the mimetic vesicles will be decorated with cell adhesion proteins to elucidate the correlations between active fluctuations, binding/unbinding rates for adhesive contacts and membrane ordering. As a result, we will be able to infer the biophysical regulators of membrane structuring in the trans and lateral directions. While providing a theoretical framework for the observed phenomena, we will make a major step forward in relating biomechanical excitations to the control of the cell state.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Dr. Etienne Loiseau