Molecular Mechanotransduction Outside and Within Cells

Mechanotransduction – the process of converting mechanical forces into immediate biochemical changes or distal changes in cell fate – is now an appreciated facet of biology. Many proteins, particularly those in fibrous extracellular and intracellular networks participate in load bearing and mechanotransduction, and recent work has highlighted the fibrous nature of these networks as key in relaying mechanical signals to cells. What if the proteins that compose the extracellular matrix or the intracellular cytoskeleton are themselves mechanotransducers by, e.g., directly revealing new enzymatic activity? How might changes in cell mechanics modify fundamental cellular processes like nuclear transport, in addition to cell fate? In this talk, I will present our work using in situ advanced microscopy to quantify protein structure in fibrous protein biomaterials in situ under different mechanical loads. We have used label-fee molecular microscopy, atomic force microscopy, Förster resonance energy transfer to show that fibrin hydrogels develop microscale spatial-structural heterogeneity that controls biochemistry and platelet activity. I will also show how changes in cell and tissue mechanics, as seen in many solid tumors, modify nuclear transport of chemotherapies. Ultimately, we aim to understand how mechanics influences physiology from the biophysics of protein networks to essential cellular functions.