Mechanical control of cell growth and differentiation

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DESCRIPTION (provided by applicant): The mechanical properties of surfaces or three dimensional matrices on which or in which cells grow have a critical influence on the morphology, transcriptional program, and function of many cell types. Recent studies show that rigidity, as quantified by the elastic modulus, determines the rates of fibroblast motility, the strength with which cells pull on their substrate, and the level of expression of such gene products as specific integrins, isoforms of actin, or class of intermediate filament. Perhaps most significantly, altered rigidity also leads to specific changes in function or preferential growth, such as activation of hepatic stellate cells and astrocytes with increased rigidity, increased neuronal process extension and branching with decreased rigidity, change from normal to abnormal structures in breast epithelia, and the differentiation pathway of mesenchymal stem cells. In some cases the magnitude of the mechanical effect can be modified by other factors such as the type of adhesion receptor involved or the amount and nature of chemical stimuli, but in other cases, the effect of mechanics dominates over chemical signaling, in that soluble stimuli that lead to specific differentiation patterns or to cell activation that are potent for cells on rigid substrates fail to exert their effect when cells are grown on softer materials. The quantitative level of rigidity to which different cell types respond can also differ by at least one order of magnitude, and within the limited data available, the significant stiffness range observed in vitro matches the rigidity of the tissue from which the primary cells derive. The goals of this project are to test the hypothesis that matrix rigidity affects cell function independently of chemical signaling, that cell-type specific mechanical responses can be used to design materials for specific biological uses, and to develop better methods by which to study the effects of material properties on cell structure and function. Effects of extracellular material stiffness may be relevant to disease processes such as fibrosis, and tumor formation in which macroscopic stiffness changes are evident in the pathologic state. The mechanical properties of the materials in which cells grow have a critical influence on the morphology and function of cells. We propose to determine optimal stiffness for specific cell functions and design soft biocompatible materials to support cell growth and function.