Investigating the cardiomyocyte rigidity sensing mechanism with micro patterned surfaces and nanopillars

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Recent discoveries have shown that cells are guided by the stiffness of their environment in a process, called mechanosensing. This influences the fate of the cells in order to form a heart, a blood vessel or other tissue. The stiffness of the heart changes during development, in disease and also during ageing, thereby affecting how well the cells in the heart can beat. However, it is still unclear how the cells in the heart measure the stiffness, or if cells from healthy and diseased hearts can sense it in the same way.In a previous study we found evidence that cells measure the stiffness at specific adhesive structures, known as costameres and focal adhesions through stretchable proteins. If the proteins are stretched, other proteins are activated to remodel certain cellular structures, called actin filaments. The actin filaments come in different varieties. Some of them are specific for cardiomyocytes, while others are also found in other cell types, such as skin or immune cells and needed to anchor the cell, or for migration. On stiff surfaces we find an increased formation of the latter structures and we believe that this will reduce the formation of the former structures (which are needed for the heart to beat). Moreover, based on others and our previous work we hypothesize that the composition of the adhesive structures changes during development and disease. Therefore, stretchable proteins with different characteristics could be located at adhesions at different times.In order to understand how the cells in the heart sense the stiffness we need a clearer picture of what proteins are present at the adhesions and how this affects the formation of the different actin filaments. Here, we want to answer these questions, by placing heart cells on synthetic substrates, which we can produce to have certain stiffnesses, or which we can use to measure the cellular forces. We can also print pattern onto these surfaces, on which the adhesive structures will form. This will allow us to monitor precisely, how much of which protein localizes to the adhesions.Further, we will disturb different signalling pathways that are activated on stiffness comparable to a healthy or diseased heart and observe the changes in the way the cells behave in response to the treatment.Together results from these experiments will lead to a deeper understanding how the heart senses the stiffness. This will allow the design of biomaterials to grow heart cells outside or inside the body to repair injuries from myocardial infarctions or other heart disease.