Computational models of extracellular matrix effects on cell migration and tissue formation

Tuesday, June 15 at 04:15am (PDT)
Tuesday, June 15 at 12:15pm (BST)
Tuesday, June 15 08:15pm (KST)

SMB2021 SMB2021 Follow Monday (Tuesday) during the "MS06" time block.
Note: this minisymposia has multiple sessions. The second session is MS07-CDEV (click here).

Share this


Magdalena Stolarska (University of St. Thomas, United States), Lisanne Rens (Delft University of Technology, Netherlands)


During development, health and disease, cells actively migrate as single cells or collectively. Vital processes in which cell migration plays a role include embryogenesis, wound healing and cancer metastasis. Cells and tissues are surrounded by the extracellular matrix (ECM), a network of proteins and fibers. Cells have complex interactions with the ECM, as they deposit matrix fibers, pull on matrix fibers, respond to various cues like fiber alignment and ECM stiffness. To understand how cell migration is guided by the ECM, computational modeling is a powerful tool. It allows us to (more readily, compared to wet-lab experiments) decompose different mechanical aspects, such as ECM stiffness, and study its effect on cell migration. In this field of mathematical biology, many models have been developed. The aim of this mini- symposium is to bring together the diverse modeling approaches of specific ECM cues, and also bridge single cell migration to collective cell behavior and whole tissues. We invite people to talk about their modeling approach and their gained biological insights. Four talks will focus on single cell migration, and four talks will be about collective cell migration and tissue formation. The studied extracellular matrix cues range from ECM density, stiffness, and fiber alignment.

Leonie van Steijn

(Leiden University, Netherlands)
"Obstacle-induced contact-inihibition of locomotion explains topotactic cell navigation in dense microenvironments"
During biological development, cancer metastasis and in the immune system, cells navigate through dense environments filled with obstacles such as other cells and the extracellular matrix. Recently, the term `topotaxis' has been introduced for the navigation of cells along topographic cues such as density gradients of obstacles. As a model of amoeboid cell motility through pores in the ECM, we study the motility of Dictyostelium discoideum cells on a substrate covered with microscopic pillars. The pillars are spaced widely enough to let the cells through and there is a gradient from densely packed pillars to more widely spaced pillars. The D. discoideum cells perform a random walk with a bias towards the more widely spaced area. A previous model based on active Brownian particles (ABP) has shown that ABPs perform topotaxis in a persistence-driven manner. However, the predicted drift is lower than measured experimentally. Here, we use a Cellular Potts model to how cell persistence mode affects topotaxis using the actin-derived persistence of the Act-model [1] and an active Brownian particle-based persistence [2]. Both persistence modes predict topotaxis, but the actin-based persistent cells show a more efficient drift.

Lisanne Rens

(Delft University of Technology, Netherlands)
"Computational models for feedback between cell shape, cell signaling and extracellular matrix"
Cell shape changes and cell migration in mammalian cells are regulated by many sig- naling proteins within the cell. Cells also interact with a meshwork of protein fibers, called the extracellular matrix (ECM), that affects signaling proteins that regulate cell motility, Rac and Rho. The feedback between Rac-Rho-ECM affects the invasiveness of melanoma cancer cells. In our models, we expand on a previous 2-compartment model (coupled ODEs in [3] and [1]) that describes Rac-Rho mutual inhibition, self-activation, the effect of each protein on the amount of contact with the ECM, and ECM activation of Rho [4]. We explore the effects of slip and catch-bond dynamics [2] for the assembly of cell-ECM adhesion. We study the full spatial dynamics in 1D and in static 2D domains, demon- strating oscillations and static/dynamic waves. These results give insight into how distinct types of cell migration emerge. By simulating the set of PDEs in a fully deformable 2D cell using a Cellular Potts model, we predict how spatially distributed signaling is coupled to cell motility. Predicted cell shapes and behavior resemble experimental observations. This full 2D model reveals how ECM anisotropy, cell stiffness, and other cell parameters affect cell migration, leading to experimentally testable predictions. Our computational models suggests insights into how the invasiveness of melanoma cells is regulated. References [1] William R Holmes, JinSeok Park, Andre Levchenko, and Leah Edelstein-Keshet. A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns. PLoS computational biology, 13(5):e1005524, 2017. [2] Elizaveta A Novikova and Cornelis Storm. Contractile fibers and catch-bond clusters: A biological force sensor? Biophys. J., 105(6):1336–1345, 2013. [3] JinSeok Park, William R Holmes, Sung Hoon Lee, Hong-Nam Kim, Deok-Ho Kim, Moon Kyu Kwak, Chiaochun Joanne Wang, Leah Edelstein-Keshet, and Andre Levchenko. Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations. Proceedings of the National Academy of Sciences, 114(28):E5750–E5759, 2017. [4] Elisabeth G. Rens and Leah Edelstein-Keshet. Cellular tango: How extracellular matrix adhesion choreographs rac-rho signaling and cell movement, 2021.

Magda Stolarska

(University of St. Thomas, United States)
"Modeling the effects of membrane mechanics on cell-substrate interaction during spreading"
It has been well established that the mechanical stiffness of the substrate with which cells interact affects various intracellular processes, including cell spread areas, speeds at which motile cells translocate, and the number and strength of cell-substrate adhesions. This mechanosensitivity is modulated through conformational changes in cell-substrate adhesion proteins that in turn regulate downstream processes, including those associated with the cell membrane (Kalappurakkal et al., Cell, 2019). Membrane dynamics, including unfolding and exocytosis from intracellular reservoirs to the lipid bilayer, is necessary for large changes in cell shape, which occur during cell spreading and motility (Figard & Sokac, BioArchitecture, 2014) and for the release of membrane tension that occurs during these shape changes (Pontes et al., J Cell Bio, 2017). The aim of this work is to understand how membrane dynamics affects the mechanics of cell spreading. To do this, we model the cell as viscous material surrounded by a viscoelastic, actively deforming membrane. The model also incorporates stress-dependent focal adhesion dynamics and their effect on actin polymerization and myosin contractility. By using the finite element method to simulate cell spreading in an axisymmetric geometry, we show that the membrane plays a critical role in controlling focal adhesions and in balancing protrusive activity and actin retrograde flow. This balance of protrusive activity not only recapitulate the three phases of cell spreading dynamics described in Gianonne et al. (Cell, 2004), but also plays a critical role in modulating the dependence of total amounts of adhesion proteins and cell spread areas on substrate stiffness.

Wanda Strychalski

(Case Western Reserve University, United States)
"Computational estimates of mechanical constraints on cell migration through the extracellular matrix"
Cell migration through a three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. Using computational simulations, we investigate two such migration mechanisms: 'push-pull' (forming a finger-like protrusion, adhering to an ECM node, and pulling the cell body forward) and 'rear-squeezing' (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm, and nucleoplasm. The model is formulated using the method of regularized Stokeslets to simulate fluid-structure interactions. We find that relations between three mechanical parameters, the cortex's contractile force, nuclear elasticity, and ECM rigidity, determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulations show the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values. Additionally, results show that the rear-squeezing mechanism is aided by hydrodynamics through a pressure gradient.

Hosted by SMB2021 Follow
Virtual conference of the Society for Mathematical Biology, 2021.