Substrate Curvature Regulates Cell Migration -A Computational Study
0
Citation
0
Reference
20
Related Paper
Cite
Cell motility has a critical role in a range of biological processes including development, immunity and disease. Navigation through complex and ever-changing environments often relies on the activity of actin-rich protrusions at the leading edge, also referred to as lamellipodia. Lamellipodia are known to exhibit areas of continuously rearranging membrane curvature, and their dynamics determines motion persistence. One group of proteins interesting in the context of membrane curvature are BAR domain proteins. However, whether and how these curvature-sensitive proteins contribute to leading edge dynamics and function, remains poorly understood. Here, we use neutrophils as a vertebrate model system of a highly migratory cell type. By combining RNAseq with a localization screen we identify two BAR proteins that are relevant for cell surface organization during migration: SH3BP1 and Snx33.
First, using fluorescent imaging and Atomic Force Microscopy, we show that SH3BP1 responds to changes in membrane mechanics and, vice-versa, modulates membrane tension. Using microfluidics, we further demonstrate that SH3BP1 is important for cell navigation through complex environments. Namely, its knockout displays increased cell speed and decision making during directed cell migration.
Next, we used the above techniques complemented with machine learning-based segmentation for time-resolved TIRF microscopy to understand the role of Snx33. We show that motion persistence and directionality, in both freely moving and environmentally constrained cells, depends on Snx33 activity. Specifically, Snx33 has an inhibitory effect on the lamellipodia dynamics by regulating WAVE2-driven actin polymerization. Our work exposes a novel mechanism by which cells steer protrusions upon encountering obstacles that facilitates efficient migration. In summary, we discovered novel functions of the curvature-sensitive proteins SH3BP1 and Snx33 in regulating cell surface mechanics and efficiency of directed cell migration.
Lamellipodium
Membrane Curvature
Live cell imaging
Cite
Citations (0)
The aim of this work is to model cell motility under conditions of mechanical confinement. This cell migration mode may occur in extravasation of tumour and neutrophil-like cells. Cell migration is the result of the complex action of different forces exerted by the interplay between myosin contractility forces and actin processes. Here, we propose and implement a finite element model of the confined migration of a single cell. In this model, we consider the effects of actin and myosin in cell motility. Both filament and globular actin are modelled. We model the cell considering cytoplasm and nucleus with different mechanical properties. The migration speed in the simulation is around 0.1 μm/min, which is in agreement with existing literature. From our simulation, we observe that the nucleus size has an important role in cell migration inside the channel. In the simulation the cell moves further when the nucleus is smaller. However, this speed is less sensitive to nucleus stiffness. The results show that the cell displacement is lower when the nucleus is stiffer. The degree of adhesion between the channel walls and the cell is also very important in confined migration. We observe an increment of cell velocity when the friction coefficient is higher.
Cite
Citations (23)
Contractility
Live cell imaging
Cite
Citations (53)
Regenerative Medicine
Dynamics
Cite
Citations (0)
Cite
Citations (46)
Abstract Cell migration is orchestrated by a complicated mechanochemical system. However, few cell migration models take account of the coupling between a biochemical network and mechanical factors. Here, we construct a mechanochemical cell migration model to study the cell tension effect on cell migration. Our model incorporates the interactions between Rac-GTP, Rac-GDP, F-actin, myosin, and cell tension, and it is based on phase field approach hence very convenient in describing the cell shape change. This model captures common features of cell polarization, cell shape change, and cell migration modes. It shows cell tension inhibits migration ability monotonically when cells are applied with persistent external stimuli. On the other hand, if random internal noise is significant, the regulation of cell tension exerts a non-monotonic effect on cell migration. As the elevation of cell tension impedes the formation of multiple protrusions hence enhances the streamline position of the cell body. Therefore the migration ability could be maximized at intermediate cell tension under random internal noise. These model predictions are consistent with our singlecell experiments and other experimental results. Statement of significance Cell migration plays a vital role in many biological processes such as tumor metastasis. It is a complicated process regulated by dynamic coupling between the biochemical network and mechanical forces. However, few cell migration models take account of both factors. Here, we construct a mechanochemical cell migration model to study how cell migration is regulated by cell tension. Our model predicts that cell tension not only inhibits cell movement under persistent external stimuli but also prompts cell migration under random internal noise when cell tension is low. Therefore an optimized cell tension could maximize the migration ability under random internal noise. We further confirmed these model predictions are consistent with our single-cell experiments and other published experimental results.
Cite
Citations (1)
Cite
Citations (0)
Cell migration is essential in many aspects of biology. Many basic migration processes, including adhesion, membrane protrusion and tension, cytoskeletal polymerization, and contraction, have to act in concert to regulate cell migration. At the same time, substrate topography modulates these processes. In this work, we study how substrate curvature at micrometer scale regulates cell motility. We have developed a 3D mechanical model of single cell migration and simulated migration on curved substrates with different curvatures. The simulation results show that cell migration is more persistent on concave surfaces than on convex surfaces. We have further calculated analytically the cell shape and protrusion force for cells on curved substrates. We have shown that while cells spread out more on convex surfaces than on concave ones, the protrusion force magnitude in the direction of migration is larger on concave surfaces than on convex ones. These results offer a novel biomechanical explanation to substrate curvature regulation of cell migration: geometric constrains bias the direction of the protrusion force and facilitates persistent migration on concave surfaces.
Cite
Citations (29)
Cell shape is known to have profound effects on a number of cell behaviors. In this paper we have studied its role in cell migration through modeling the effect of cell shape on the cell traction force distribution, the traction force dependent stability of cell adhesion and the matrix rigidity dependent traction force formation. To quantify the driving force of cell migration, a new parameter called the motility factor, that takes account of the effect of cell shape, matrix rigidity and dynamic stability of cell adhesion, is proposed. We showed that the motility factor depends on the matrix rigidity in a biphasic manner, which is consistent with the experimental observations of the biphasic dependence of cell migration speed on the matrix rigidity. We showed that the cell shape plays a pivotal role in the cell migration behavior by regulating the traction force at the cell front and rear. The larger the cell polarity, the larger the motility factor is. The keratocyte-like shape has a larger motility factor than the fibroblast-like shape, which explains why keratocyte has a much higher migration speed. The motility factor might be an appropriate parameter for a quantitative description of the driving force of cell migration.
Tractive force
Rigidity (electromagnetism)
Cell polarity
Cite
Citations (59)
A fascinating feature of eukaryotic cells is their ability to move. Cellular motility controls crucial biological processes such as, e.g., cellular nourishment, wound healing, tissue growth, pathogen removal, or metastatic disease. Cell migration through biological tissues is an exceedingly complex process, which is usually understood as a continuous cycle of five interdependent steps, namely: protrusion and elongation of the leading edge driven by actin polymerization; cell-matrix interaction and formation of focal contacts via transmembrane adhesion proteins; extracellular matrix degradation by cell surface proteases; actomyosin contraction generated by active myosin II bound to actin filaments; and detachment of the trailing edge and slow glide forward. Cell migration may be directed by different external stimuli perceived through the cell’s membrane via membrane proteins. Those stimuli, which may take the form of chemical cues or changes in the physical properties of the environment, produce a cellular response that modifies the motile behavior of the cell. Moreover, motile cells may exhibit a number of morphological variants, called modes of migration, as a function of endogenous and exogenous factors such as, e.g., cell-cell and cell-extracellular matrix adhesion, extracellular matrix degradation, orientation of the extracellular matrix fibers, or the predominant cytoskeleton structure. The prominent modes of individual cell migration are mesenchymal, amoeboid, and blebbing motion. Cells can compensate the loss of a particular motile ability by developing migratory strategies, which include the transition between different modes of cell migration. In this thesis we develop three mathematical models of individual cell migration. The models account for the interactions between the cytosolic, membrane, and extracellular compounds involved in cell motility. The motion of the cell is driven by the actin filament network, which is assumed to be a Newtonian fluid subject to forces caused by the cell motion machinery. Those forces are the surface tension of the membrane, cell-substrate adhesion, actin-driven protrusion, and myosin contraction. Also, a repulsive force acting on the cell’s membrane accounts for the interaction with obstacles, which may represent fibers or walls. The models are grounded on the phase-field method, which permits to solve the partial-differential equations posed on the different domains (i.e., the cytosol, the membrane, and the extracellular medium) by using a fixed mesh only. The solution of the higherorder equations derived from the phase-field theory entails a number of challenges. To overcome those challenges, we develop a numerical methodology based on isogeometric analysis, a generalization of the finite element method. For the spatial discretization we employ B-splines as basis functions, which possess higher-order continuity. We propose a time integration algorithm based on the generalized- method. The first model focuses on mesenchymal motion. The model proposes a novel description of the actin phase transformations based on a free-energy functional. The results show that the model effectively reproduces the behavior of actin in keratocytes. The simpler case of cell migration in flat surfaces produces stationary states of motion that are in good agreement with experiments. Also, by considering obstacles, we are able to reproduce complex modes of motion observed in microchannels, such as, e.g., oscillatory and bipedal motion. The second model is used to analyze the spontaneous migration of amoeboid cells. The model accounts for a membrane-bound species that interacts with the cytosolic compounds. The model results show quantitative agreement with experiments of free and confined migration. These results suggest that coupling membrane and intracellular dynamics is crucial to understand amoeboid motion. We also show simulations of a cell moving in a three-dimensional fibrous environment, which we interpret as an initial step toward the computational study of cell migration in the extracellular matrix. The third model focuses on chemotaxis of amoeboid cells. The model captures the interactions between the extracellular chemoattractant, the membrane-bound proteins, and the cytosolic components involved in the signaling pathway that originates cell motility. The two-dimensional results reproduce the main features of chemotactic motion. The simulations unveil a complicated interplay between the geometry of the cell’s environment and the chemoattractant dynamics that tightly regulates cell motility. We also show three-dimensional simulations of chemotactic cells moving on planar substrates and fibrous networks. These examples may constitute a first approach to simulate cell migration through biological tissues.
Cell membrane
Leading edge
Cite
Citations (1)