Final Report Summary - MECHANOCHEM SWITCHES (Switching the structure-function relationship of proteins by mechanical forces: physiological and technological implications)
The question how cells and tissues feel mechanical forces and the mechanical properties of their environments is one of the big mysteries in biology. This field of mechanobiology has gained major momentum only very recently since new methodologies, many of which were adapted from the microfabrication and nanotechnology communities, made it possible to interrogate at the molecular and cellular level how mechanical forces applied to proteins can switch their structure-function relationship (mechano-chemical switches). Since mechanotransduction processes control most elemental steps, from cell adhesion to gene expression, our central focus was to decipher the underpinning structural mechanisms how tensile forces acting on proteins outside and inside of cells are translated into biochemical signal changes (mechano-chemical signal conversion) and how this can alter cellular behavior (mechanotransduction). Cells thereby recognize physical features in their environments by exploiting mechanical forces generated by their motors which pull on distal extracellular anchoring points as reviewed recently (Schoen, Pruitt, Vogel, The yin-yang of rigidity sensing, Annual Review of Materials Research, Vol. 43 (2013), 589-618. What cells locally feel furthermore depends not only on the displacement of a material, but also on the stability of molecular interactions, on the conversion of mechanical forces to biochemical signals by stretching proteins into structural intermediates (mechano-chemical signal conversion), and on the micro- and nanoscopic features of the extracellular protein coating as illustrated by the following studies:
This ERC Advanced Grant enabled us to make a few really important discoveries: First, we could show that the binding of bacterial adhesins to tissue fibers made of fibronectin can be switched off by stretching the fibers (Nature Communications 2010). A follow-up study allowed us to develop a mechanosensitive library of bacterial derived peptides, some of which bind in a strain-dependent manner to fibronectin fibers (Nanoletters in 2012). Second and with a focus on fibronectin (since this adhesion molecule is highly upregulated in early development, wound sites and cancer), we explored how the stretching of extracellular matrix fibers might regulate cell functions. Our major findings include the observation made in a large European collaboration that cells not only fee the rigidity of a material, but sense how the protein layer is physically coupled to the substrate (Nature Materials 2012). This was followed up by showing that the osteogenic differentiation of human mesenchymal stem cells is upregulated when exposing them to stretched fibronectin fibers (Scientific Reports 2013). When asking how fibronectin might regulate early processes in development, we made another discovery on factors that regulate the differentiation of mouse embryonic stem cells (EU patent filed October 2013). We also started to test how well functional relationships established in 2D cell culture are predictive to cell behaviour and function in three-dimensional tissues, and did so by exploiting micro-tissue model systems (Integrative Biology 2012). Finally, topography sensing is one of the most fundamental processes that cells exploit to interact with their environments, either during development, wound healing or metastatic invasion. Since little was known about the role of filopodia in topography sensing, especially within nanofibrillar environments, we have grown highly flexible hairy silicon nanowires on micropatterned islands on otherwise flat glass surfaces and coated them both with the extracellular matrix protein fibronectin and discovered a mechanical mechanism how cells exploit filopodia to recognized nanotopographies (Scientific Reports 2013). In summary, we identified many new molecular mechanisms how cells sense forces and respond to material properties. Such discoveries how proteins act as mechano-chemical switches are therefore prone to impact many fields of science, technology and medicine.
This ERC Advanced Grant enabled us to make a few really important discoveries: First, we could show that the binding of bacterial adhesins to tissue fibers made of fibronectin can be switched off by stretching the fibers (Nature Communications 2010). A follow-up study allowed us to develop a mechanosensitive library of bacterial derived peptides, some of which bind in a strain-dependent manner to fibronectin fibers (Nanoletters in 2012). Second and with a focus on fibronectin (since this adhesion molecule is highly upregulated in early development, wound sites and cancer), we explored how the stretching of extracellular matrix fibers might regulate cell functions. Our major findings include the observation made in a large European collaboration that cells not only fee the rigidity of a material, but sense how the protein layer is physically coupled to the substrate (Nature Materials 2012). This was followed up by showing that the osteogenic differentiation of human mesenchymal stem cells is upregulated when exposing them to stretched fibronectin fibers (Scientific Reports 2013). When asking how fibronectin might regulate early processes in development, we made another discovery on factors that regulate the differentiation of mouse embryonic stem cells (EU patent filed October 2013). We also started to test how well functional relationships established in 2D cell culture are predictive to cell behaviour and function in three-dimensional tissues, and did so by exploiting micro-tissue model systems (Integrative Biology 2012). Finally, topography sensing is one of the most fundamental processes that cells exploit to interact with their environments, either during development, wound healing or metastatic invasion. Since little was known about the role of filopodia in topography sensing, especially within nanofibrillar environments, we have grown highly flexible hairy silicon nanowires on micropatterned islands on otherwise flat glass surfaces and coated them both with the extracellular matrix protein fibronectin and discovered a mechanical mechanism how cells exploit filopodia to recognized nanotopographies (Scientific Reports 2013). In summary, we identified many new molecular mechanisms how cells sense forces and respond to material properties. Such discoveries how proteins act as mechano-chemical switches are therefore prone to impact many fields of science, technology and medicine.