Periodic Reporting for period 1 - TopCellComm (Topography-Mediated Cell Communication)
Reporting period: 2023-01-01 to 2024-12-31
Mechanical interactions of cells with their environment are fundamental for cell- sensing and decision making in both development and homeostasis. Despite being widespread and acknowledged, the mechanisms by which cells perceive and generate forces remain elusive. In particular, the dynamic eedback that arises from interactions between cells and their substrate remains unexplored.
In tissues, cells rely on the balance between internal pulling forces, dictated by tensions and cytoskeleton, and external forces that arise from the microenvironment. Mechanical forces impact protein distribution and gene expression within cells, inducing specific cell functions. For instance, stretching the cell results in enhanced cell division and differentiation in stem cells, whereas that mechanical compression governs the cell death and its subsequent expulsion from a tissue. Furthermore, cells not only respond to the environment, but actively modify it by exerting contractile forces generated by cross-bridging interactions of actin and myosin filaments while moving. Contractile forces cause rapid and long-ranged topographic anisotropies in the substrate, such as wrinkles or strains, which provide environmental cues and the means for substrate-mediated cell interactions. Such topography-mediated mechanical cell-cell communication has enormous potential both for improved medical interventions and for new strategies in regenerative medicine in which mechanical signals will be used o direct the repair of tissues and organs that have been damaged by trauma or disease.
The overarching goal of this project is to model the phenomenon, in which cells autonomously exploit folding and topographical restructuring of their underlying substrates as a means of self-induced guidance and describe predicted topography-mediated cell-cell communication.
In tissues, cells rely on the balance between internal pulling forces, dictated by tensions and cytoskeleton, and external forces that arise from the microenvironment. Mechanical forces impact protein distribution and gene expression within cells, inducing specific cell functions. For instance, stretching the cell results in enhanced cell division and differentiation in stem cells, whereas that mechanical compression governs the cell death and its subsequent expulsion from a tissue. Furthermore, cells not only respond to the environment, but actively modify it by exerting contractile forces generated by cross-bridging interactions of actin and myosin filaments while moving. Contractile forces cause rapid and long-ranged topographic anisotropies in the substrate, such as wrinkles or strains, which provide environmental cues and the means for substrate-mediated cell interactions. Such topography-mediated mechanical cell-cell communication has enormous potential both for improved medical interventions and for new strategies in regenerative medicine in which mechanical signals will be used o direct the repair of tissues and organs that have been damaged by trauma or disease.
The overarching goal of this project is to model the phenomenon, in which cells autonomously exploit folding and topographical restructuring of their underlying substrates as a means of self-induced guidance and describe predicted topography-mediated cell-cell communication.
During this project we have developed a mathematical framework that captures cell-generated stresses and nonlinear deformations in the soft substrate. To do so, we have coupled Foppl-von Karman equations for thin plate deformation with a 3D phase-field model of a contractile cell. Our model accurately and efficiently reproduces wrinkling patterns that arise from cell-generated isotropic stresses. We have calibrated the model using wrinkle-force-microscopy single cell experimental data and performed an extensive sensitivity analysis, elucidating the roles of material properties of the substrate as well as cell properties, such as shape and cotnractility, on the wrinkle pattern formation.
Furthermore, by analysing experimental traction force microscopy data, we have explored different stress modes that cells exert on substrate and identified the importance of considering quadrupolar stresses. In order to understand the role of quadrupolar activity on the collective behaviour of active nematics, we have developed a corresponding continuum model and, together with newly established collaboration with experimentalists, uncovered new physical mechanism towards control of synthetic active materials, such as microtubule kinesin protein motors. We then took another step further and incorporated time-dependent changes coupling between active cells and their evironment (extracellular matrix) into continuum model to uncover the role of stress buildup during chick embryo muscle development, which led to another successful collaboration with experimentalists.
Finally, using the developed 3D model of a cell, we have investigated the role of contractility in the interactions between multiple cells and substrate. We have extended our novel model to the system of two cells and studied the emergent wrinkling patterns in soft deformable substrate. Moreover, we elucidated the role of cell contractility and cell-cell adhesion when cells reside on solid substrate with gaps, mimicking soft collagen substrates. This allowed us to determine which mechanical properties lead to apical versus basal extrusion in the monolayers of MDCK cells.
Furthermore, by analysing experimental traction force microscopy data, we have explored different stress modes that cells exert on substrate and identified the importance of considering quadrupolar stresses. In order to understand the role of quadrupolar activity on the collective behaviour of active nematics, we have developed a corresponding continuum model and, together with newly established collaboration with experimentalists, uncovered new physical mechanism towards control of synthetic active materials, such as microtubule kinesin protein motors. We then took another step further and incorporated time-dependent changes coupling between active cells and their evironment (extracellular matrix) into continuum model to uncover the role of stress buildup during chick embryo muscle development, which led to another successful collaboration with experimentalists.
Finally, using the developed 3D model of a cell, we have investigated the role of contractility in the interactions between multiple cells and substrate. We have extended our novel model to the system of two cells and studied the emergent wrinkling patterns in soft deformable substrate. Moreover, we elucidated the role of cell contractility and cell-cell adhesion when cells reside on solid substrate with gaps, mimicking soft collagen substrates. This allowed us to determine which mechanical properties lead to apical versus basal extrusion in the monolayers of MDCK cells.
This interdisciplinary project produced several results that has potential impact beyon the state of the art. First, we have developed a numerical code that couples the equations describing thin plate deformation to the active stresses exerted by cells. This opens new opportunities for biophysicists and mathematicians working on cell motility and cell-substrate interactions. As the code is open source, it will complement both theoretical and experimental academic studies. Secondly, this project unraveled several new mechanical cues that shape cell-environment interactions. This provides potential routes towards controlling active materials and engineering novel biomaterials for both academia and industrial applications. Furthermore, since this project provided insights towards our understanding of diseases, it has direct impact on the healthcare.