![]() Numerous proteins and protein complexes required for responding to substrate stiffness, such as the actomyosin network, small GTPases, protein phosphatases, and integrin adhesion sites have been identified, but the mechanism by which forces govern the interactions among these proteins are not yet defined. Not all cell types respond to stiffness changes in the same way, but many including endothelial cells, fibroblasts, mammary epithelial cells astrocytes, macrophages and mesenchymal stem cells, exhibit increased spreading and adhesion on stiffer substrates compared to softer ones. Over the last decade it has been demonstrated that a variety of tissue-forming cells can both sense the stiffness of their substrate and apply a controlled force onto that substrate. Thus cells are acutely responsive to the nonlinear elasticity of their substrates and can manipulate this rheological property to induce patterning. Atomic force microscopy and rheology confirm that these strains locally and globally stiffen the gel, depending on cell density, and this effect leads to long distance cell-cell communication and alignment. Time lapse microscopy reveals that fibroblasts and human mesenchymal stem cells on fibrin deform the substrate by several microns up to five cell lengths away from their plasma membrane through a force limited mechanism. On nonlinear strain-stiffening fibrin gels, the same cell types become maximally spread even when the low strain elastic modulus would predict a round morphology, and cells are influenced by the presence of neighbors hundreds of microns away. As cell density increases, individual cells retain the same stiffness-dependent differences unless they are very close or in molecular contact. ![]() Most tissue cells grown in sparse cultures on linearly elastic substrates typically display a small, round phenotype on soft substrates and become increasingly spread as the modulus of the substrate increases until their spread area reaches a maximum value.
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