Mechano-modulation of cell adhesion nanoplatforms

Through evolution, living cells have developed the exquisite ability to sense, transduce and integrate mechanical and biochemical signals (i.e., mechanobiology) to generate appropriate cell response. Intensive research in the last years has established the importance of mechanobiology in a broad range of biological processes that include differentiation, developmental morphogenesis, homeostasis and immunity. Similarly, it is becoming clear that many apparently unrelated diseases (e.g. atherosclerosis, cancer progression, osteoporosis, fibrosis …) share as common feature an abnormal integration of mechanical and chemical stimuli. The interest in mechanobiology is therefore not only fundamental, but driven by the need to identify the mechanisms that cause these diseases.

Mechanosensing and mechanotransduction start at the plasma membrane with the dynamic interaction of different molecules and their assembly into mechanosensitive nanoplatforms, in a process that takes place at the nanoscale. However, assessing these small scales in a dynamic fashion within the complexity of living cells is highly challenging. For this, we particularly focus on different mechano-sensitive integrin receptors located within focal adhesions (FAs). Exploiting different forms of super-resolution microscopy (STORM, DNA-PAINT and STED) we discovered a highly hierarchical spatial organization and differential activation of integrin receptors inside FAs. Interestingly, integrin activation and function appear to be spatially regulated, implying that possibly mechanotransduction is also differentially controlled, depending on the type of integrin and its physical location inside FAs. These exciting results have opened up new questions that we are currently exploring: what are the rules that govern this well-defined organisation? What is the nature of this organisation-function relationship? What is the effect of external mechanical inputs?, and, importantly, are the phenomena that we have observed at the levels of individual molecules and nanoscale required for overall cell response?