Download or read book Structural Heterogeneity in Ecm and Its Effect on Cell Mechanosensing written by Maria Proestaki and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The extracellular matrix (ECM) provides structural support to tissues, while exerting biochemical and mechanical signals to resident cells. Such mechanical signals, the most familiar being matrix stiffness, regulate cell morphology, differentiation, migration, proliferation and gene expression. Therefore, studying the mechanical properties of the extracellular matrix is crucial to understanding cell behavior. With collagen type I being the most abundant protein found in mammalian tissues, prior works have studied its mechanical properties at the macroscale and reported a strong deviation from linear elasticity, exhibiting strain stiffening and compression weakening behavior. However, to better understand cell-matrix interactions more information about the matrix at the length scale of a cell is needed. Here we design an experimental method to quantify matrix stiffness at the length scale of a cell while accounting for matrix nonlinearity. We use spherical particles made of an active hydrogel that contract when heated, mimicking cell contraction. Results showed that the matrix stiffness is highly heterogeneous at the length scale of a cell, with values ranging by a factor of 3. Next, we examine the effect of matrix heterogeneity in structure on cell ability to sense other stiffer inclusions in the matrix, such as ducts, tumors or regions of abnormally high stiffness. Using a combination of experiments and modeling, we determine the extent to which matrix heterogeneity disrupts cell sensing of a locally stiff feature in the matrix. We found that the propagation of mechanical cues through the matrix depends on length scale, with single cells able to sense only the stiffness of the nearby fibers and multicellular structures, such as tumors, also sensing the stiffness of distant matrix features. Lastly, another matrix component, hyaluronic acid, is incorporated in our experiments to test its effect on fibrous collagen mechanics at the length scale of a cell. The addition of hyaluronic acid was found to make displacements in fibrous collagen to decay faster with distance from localized loads, closer to linear elasticity prediction, indicating a more linear matrix behavior with less compression softening. Also, collagen-hyaluronic acid matrices decrease the ability of fibrous collagen to hold permanent displacements, creating a more elastic matrix. By applying these findings to study matrix remodeling due to localized forces, we found that hyaluronic acid partially--but not fully--inhibited matrix remodeling. These results are evidence that there must be another mechanism for mechanical remodeling, which provides new experimental evidence supporting prior working showing that mechanical remodeling can be described by a phase transition associated with instability caused by compression softening. Overall, the findings of this thesis highlight the importance of length scale when trying to understand cell-matrix interactions. Small changes in local matrix structure can result in different behavior of neighboring cells, highlighting the importance of local matrix mechanics in understanding cell behavior in normal or diseased tissues.