Matrix Softening Controls Stretch-Induced Cellular Memory and Fibroblast Activation

Mechanical stretching of living tissues can activate long-lived changes in tissue cells such as fibroblasts, increasing their contractility and initiating phenotypic transformations. Increased mechanical stimulus typically leads to monotonically increasing activation of fibroblasts cultured in 2D, but activation levels are difficult to predict for cells in 3D fibrous tissues, leading to variable outcomes in procedures such as skin grafting. Here we report that the source of this variation is cell-extracellular matrix (ECM) interactions and their variation with the duration and magnitude of applied stretch, and present a model that can predict the degree to which stretch will either increase or decrease long-term activation levels of fibroblasts cultured within a stretched, three-dimensional collagen matrix. Combining experimental and mathematical approaches across multiple scales, we show that the viscoplasticity of the ECM regulates this nonmonotonic, long-term cell activation. Results demonstrate that feedback between cell and ECM determines how cells retain memory of mechanical stretch.