CDEV Subgroup Contributed Talks

Adriana Zanca

The University of Melbourne

"Comparison of locally and globally acting wound closure mechanisms"

Epidermal wound closure is a complex process involving the coordination of many mechanisms across multiple spatial scales. In this work we use cell-based modelling to investigate wound closure mechanisms acting on whole-wound and localised scales. We begin by exploring spatial effects on wound closure - specifically tissue compression due to cell division events and individual cellular compression. We then consider two key wound healing mechanisms: purse-string closure and cell crawling. The purse-string mechanism involves contraction of the acto-myosin cables in cells adjacent to the wound edge whereas the cell crawling mechanism describes active cellular migration due to lamellipodial protrusions. Previous cell-based models of wound healing have attempted to describe the purse-string mechanism at a cellular level scale. However, it has been established that purse-string behaviour occurs on a whole-wound scale. In particular, an actomyosin cable forms around the entire wound edge and contracts ‘globally’ during closure. In this work, we formulate a wound-scale model for purse-string closure and compare it to a locally acting model. Finally, we propose two models for cell crawling: one where cells respond to their local environment and another in which cells actively migrate in response to a global cue. We compare the two models and discuss the relative benefits of each. We conclude by summarising the overall differences between globally and locally acting mechanisms and propose more realistic extensions of each model.
Additional authors: Jennifer Flegg, The University of Melbourne; James Osborne, The University of Melbourne

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Gordon R. McNicol

University of Glasgow

"A one-dimensional continuum model for focal adhesion and ventral stress fibre formation"

To function and survive, cells need to be able to sense and respond to their local environment in a process called mechanotransduction. Crucially, mechanical and biochemical perturbations to a cell can initiate signaling cascades which can induce, among other responses, cell growth, apoptosis, proliferation and differentiation - focal adhesions and actomyosin stress fibres are at the heart of this process. The formation and maturation of these structures (connected by a positive feedback loop) is pivotal in non-motile cells, where stress fibres are generally of ventral type, interconnecting focal adhesions and producing isometric tension. We have formulated a one-dimensional bio-chemo-mechanical continuum model to describe the coupled formation and maturation of ventral stress fibres and focal adhesions. We use a set of reaction-diffusion-advection equations to describe three sets of biochemical events: the polymerisation of actin and bundling and activation of the resultant fibres; the formation and maturation of adhesions between the cell and substrate; and the upregulation of certain signaling proteins in response to focal adhesion and stress fibre formation. The evolution of these key proteins is then coupled to a Kelvin-Voigt viscoelastic description for the cell cytoplasm and for the ECM. We employ this model to understand how cells respond to external and intracellular cues in vitro. We are able to replicate various experimentally observed phenomena including demonstrating that stress fibres exhibit non-uniform striation, cells form weaker stress fibres and focal adhesions on compliant surfaces and myosin II inhibition leads to disruption of focal adhesions. The model hence provides a platform for systematic investigation into how the cell biochemistry and mechanics influence the growth and development of the cell and facilitates prediction of internal cell measurements that are difficult to ascertain experimentally, such as stress distribution.
Additional authors: Peter S. Stewart, School of Mathematics and Statistics, University of Glasgow; Matthew J. Dalby, School of Molecular Biosciences, University of Glasgow

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Kaiyun Guan

University of North Carolina at Chapel Hill

"How do yeast regulate polarity behavior to ensure successful mating?"

Many cells adjust the direction of polarized growth or migration in response to external directional cues. The yeast Saccharomyces cerevisiae orient their cell fronts (also called the polarity sites) up pheromone gradients in the course of mating. However, the initial polarity site often misaligns with the pheromone gradient. Therefore, to track pheromone gradients requires reorientation of the polarity site. During this reorientation phase, the polarity site displays erratic assembly-disassembly behavior as it moves around the cell cortex. The mechanisms underlying this dynamic behavior remain poorly understood. Particle-based simulations of the core polarity circuit revealed that molecular-level fluctuations are insufficient to overcome the strong positive feedback required for polarization and generate relocating polarity sites. Inclusion of a pheromone-sensing pathway that acts over longer time scales than the pathways associated with the core polarity circuit generated a mobile polarity site with properties similar to those observed experimentally. This sensing pathway couples polarity establishment to the gradient sensing and, surprisingly, it also has a positive feedback architecture because polarity factors direct secretion of new pheromone receptors to the cell membrane. This second positive feedback loop also allows cells to stabilize their polarity site once the site is aligned with the pheromone gradient.
Additional authors: Daniel J. Lew, Department of Biology, Massachusetts Institute of Technology; Timothy C. Elston, Department of Pharmacology and Computational Medicine Program, University of North Carolina at Chapel Hill.

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Sharon B. Minsuk

Indiana University, Bloomington

"Modeling the Mechanical Forces Driving Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly"

Epithelial shape change is of major importance in early development across the animal kingdom. Using a new particle-based simulation framework, Tissue Forge (https://compucell3d.org/TissueForge), we set out to model the epithelial morphogenesis of zebrafish epiboly, in which the blastoderm epithelium, sitting atop a large yolk cell, gradually stretches downward over the yolk to completely engulf it. The forces driving this extension and shape change are believed to be generated within the yolk cell and act on the epithelial margin. We use single particles to represent cells, and global potentials and bonds to represent cellular interactions such as adhesion and tissue tension. Tissue extension occurs when exogenous force from the yolk cell is strong enough to overcome the internal tension of the epithelial layer. Dynamic, stochastic remodeling of intercellular bonds, with constraints on the neighborhood topology, allows for viscoelastic tissue deformation and cell rearrangement in response to exogenous forces, while maintaining tissue integrity. Stress and strain patterns within the epithelium show a spatial and temporal dependence on model parameters and may help to distinguish between hypothesized force generation mechanisms.
Additional authors: T.J. Sego; James A. Glazier

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