Fibrosis is a central component of numerous major diseases and is implicated in an estimated 45% of all deaths in the developed world. Hallmarks of fibrosis include myofibroblast (MF) induction, excessive MF proliferation and matrix synthesis, and stiffening or contraction of the extracellular matrix (ECM), but how these changes are interrelated and feedback to reinforce the fibrotic process is not understood. This is in part because we lack a fundamental understanding of how cells sense, mechanically respond to, and in turn alter the structure and mechanics of their surroundings during fibrosis. To fill this gap in our knowledge and develop treatments that target the mechanisms of fibrosis, we need experimental approaches that allow us to 1) accurately capture the fibrous structure and mechanical behavior of tissues, and 2) monitor the mechanical forces that drive MF differentiation, proliferation, and subsequent fibrotic stiffening. The overall focus of the proposed work is to connect intracellular and extracellular mechanics during the initiation and reinforcement of MF induction and proliferation. We will measure MF contractile forces in a newly established synthetic ECM that is fibrous, mechanically tunable, and can be reorganized by cells. Using this platform, we will examine whether TGF- induces RhoA-mediated fibril reorganization to increase traction force generation and subsequent MF induction and proliferation. With an understanding of how MF induction and proliferation is initiated, we will proceed to examine how increased MF cell density reinforces fibrotic changes during the R00 phase. We will determine whether tension within the fibrillar ECM generated by high densities of contractile MFs spurs further MF induction. Next, we will examine the effect of high MF density on fibrillar network stiffening via ECM synthesis, and query whether this in turn also promotes MF induction. This work will shine light on biophysical mechanisms common to fibrotic changes accompanying numerous diseases, and may provide a test bed for therapeutics that can disrupt this process.
During fibrosis, abnormal myofibroblasts impair organ function by stiffening tissues, but how tissue stiffening causes healthy cells to become myofibroblasts is not understood. The proposed work will measure cellular forces in a synthetic fibrous tissue model to study the underlying mechanics of myofibroblast transformation, with the long term goal of establishing a test bed for therapeutics that target this process to stop fibrosis.
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