The role of cell surface mechanics in activating the mechanosensitive ion channel Piezo1

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Our body senses both chemical signals, such as smell molecules, and mechanical signals, such as pressure. In a similar way, most cells in our body sense and respond to both chemical and mechanical signals in their environment. However, while our understanding of chemical signalling has increased tremendously over the past decades, much less is currently known about how cells 'feel' mechanical signals such as forces or tissue stiffness. Cells are surrounded by a thin shell mainly consisting of lipids, which is called cell membrane. When cells are exposed to forces, which might, for example, come from a neighbouring cell pulling on it or shear forces exerted by blood flowing by, the cell membrane is deformed. This deformation may be registered by highly specialised proteins located in the membrane that act as force sensors. One of the most important force sensing proteins in the cell membrane is an ion channel (i.e., a 'hollow' protein traversing the membrane that may open like a gate to let ions pass through) called Piezo1. Piezo1 is thought to be activated by an increase in membrane tension, i.e., a force acting in parallel to the membrane, which for example increases when water flows into cells, like the membrane of a balloon gets more tense when air is blown in. However, direct evidence for an activation of Piezo1 by changes in membrane tension in living cells is still scarce, and recent data challenge this assumption. Furthermore, if and how membrane tension in cells changes in response to mechanical signals such as the stiffness of their environment is still poorly understood. The focus of this proposal is on identifying how Piezo1 is activated in response to substrate stiffness in living cells. To address this, a team with long-standing experience in cell biology, mechanobiology and physical biology will develop and exploit diverse approaches to measure and perturb membrane tension either across whole cells or just locally. We will culture cells on custom-built soft substrates and monitor Piezo1 activity in response to well-defined mechanical signals and manipulation of cellular components involved in force generation and force transmission. Ultimately, we will test how cell surface mechanics controls mechanical signalling through Piezo1 in frog embryos, which has important implications for developmental and pathological processes which are accompanied by changes in tissue mechanics, such as neurodegenerative diseases. Any insights gained into how Piezo1 translates a mechanical signal into an intracellular response might reveal new targets for drug development to interfere with age-related problems such as dementia, or even with regenerative processes after neural injury and neurodegenerative diseases, where tissue mechanics - and hence Piezo1-mediated signalling - changes.