Morphogenesis, the shaping of organisms, organs and tissues is driven by chemical signals and physical forces. It is still poorly understood how cells are able to collectively form intricate patterns, like for instance vascular networks. In particular, we were concerned with how interactions between the cell and the extracellular matrix (a protein network surrounding tissues that supports cells and guides cell migration) regulates morphogenesis. My PhD has mainly focused on how physical forces may drive morphogenesis. Lab experiments have shown that the mechanical properties of the matrix, such as its stiffness, regulate morphogenesis. In this presentation I will focus on my work on mechanical cell-matrix interactions. We developed a multiscale model that describe cells and the matrix and their interactions through physical forces. In this model, cells are represented by the Cellular Potts Model. The deformations in the ECM are calculated using a Finite Element Method. We model a mechanical feedback between cells and the ECM, where 1) cells pull on the ECM, 2) strains are generated in the ECM, and 3) cells preferentially extend protrusions oriented with strain. Similar to lab experiments, simulations show that cells are able to generate vascular like patterns on matrices of intermediate stiffness. Lab experiments where the matrix is uniaxially stretched, show that cells orient parallel to stretch. Model results on cells on a stretched matrices with and without traction forces indicate that cell traction forces amplify cell orientation parallel to stretch. Furthermore, they allow cells to organize into strings in the direction of stretch. I will also show an extension of this model. Stiffness sensing is mediated by transmembrane integrin molecules, which behave as ‘catch bonds’ whose strength increases under tension. Focal adhesions, which are large assemblies of these integrins, grow larger on stiffer substrates. We included such dynamics in our multiscale model. This second model explains how cell shape depends on matrix stiffness and how cells are able to durotact (move up a stiffness gradient). This model gives a more molecular understanding of how cells respond to matrix stiffness.

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