The Role of Extracellular Matrix Fibrils in Stiffness Changes and Growth Factor Tethering during Fibrosis

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Fibrosis is a pathological condition in which tissue healing proceeds in an uncontrolled manner. It has been estimated that nearly half of all deaths in the western world can be attributed to fibrosis. Fibrosis occurs in nearly every organ, including liver, kidney, heart, skin, and lung. While it is well appreciated that fibrosis is associated with organ failure in many disease states, there are few treatments that have proven successful. This award will support fundamental work in this area by studying the mechanobiology of fibrosis. Mechanobiology is a growing field in which researchers investigate the role of mechanical properties of cells and tissues in disease progression. The research team hypothesize that fibrosis proceeds by initially increasing the stiffness of the tissue, which then leads to the generation of larger contractile forces in local cells, which in turn drives the assembly of more stiff fibrotic tissue, resulting in uncontrolled progression of fibrosis. This research has the potential to discover important insights in fibrosis treatment by investigating the mechanical signaling that underlies fibrosis progression. While there are tissue-specific aspects of fibrosis, there are several common themes that are seen regardless of tissue type or disease: cells at the site of fibrosis generate larger contractile forces, they secrete increased levels of extracellular matrix proteins, and they have elevated activation of the Transforming Growth Factor-beta pathway, which is implicated in many diseases, but is also critical in wound healing. Progression of fibrosis drives tissue stiffening, which ultimately disturbs tissue structure and impairs organ function. The research team hypothesizes that these common events are integrated through cell-driven assembly of the extracellular matrix protein fibronectin into elastic fibrils. These fibrils are assembled in response to cell-generated contractile forces and possess a growth-factor binding site that binds several growth factors, including Transforming Growth Factor-beta, with nanomolar affinity. The research team will investigate the hypothesis that fibronectin fibrils facilitate fibrosis by both increasing tissue stiffness in fibrotic tissue and localizing Transforming Growth Factor-beta to the cell surface via tethering to fibronectin fibrils. The team will investigate this hypothesis through the use of microfabricated pillar arrays that can quantify both cell-generated contractile forces and assembly of fibronectin fibrils. A novel tool will also be developed to quantify the stiffness of in vitro assembled extracellular matrix.