James A. Glazier

Anomalous diffusion and non-Gaussian velocity distribution of Hydra cells in cellular aggregates

We study the center of mass motion of single endodermal Hydra cells in two kinds of cellular aggregates: endodermal and ectodermal. The mean square displacement displays anomalous super-diffusion with 〈x2〉∼tα where α>1. The velocity distribution function is non-Gaussian and fits well the q-distribution function of velocities within the framework of the non-extensive thermostatistics proposed by Tsallis. Our results indicate that cell motion in two-dimensional cellular aggregates can be described by a “correlated-type” anomalous diffusion.

3D multi-cell simulation of tumor growth and angiogenesis.

We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors.

CompuCell, a multi-model framework for simulation of morphogenesis

MOTIVATION CompuCell is a multi-model software framework for simulation of the development of multicellular organisms known as morphogenesis. It models the interaction of the gene regulatory network with generic cellular mechanisms, such as cell adhesion, division, haptotaxis and chemotaxis. A combination of a state automaton with stochastic local rules and a set of differential equations, including subcellular ordinary differential equations and extracellular reaction-diffusion partial differential equations, model gene regulation. This automaton in turn controls the differentiation of the cells, and cell-cell and cell-extracellular matrix interactions that give rise to cell rearrangements and pattern formation, e.g. mesenchymal condensation. The cellular Potts model, a stochastic model that accurately reproduces cell movement and rearrangement, models cell dynamics. All these models couple in a controllable way, resulting in a powerful and flexible computational environment for morphogenesis, which allows for simultaneous incorporation of growth and spatial patterning. RESULTS We use CompuCell to simulate the formation of the skeletal architecture in the avian limb bud. AVAILABILITY Binaries and source code for Microsoft Windows, Linux and Solaris are available for download from http://sourceforge.net/projects/compucell/

Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth.

Blood vessels form either when dispersed endothelial cells (the cells lining the inner walls of fully formed blood vessels) organize into a vessel network (vasculogenesis), or by sprouting or splitting of existing blood vessels (angiogenesis). Although they are closely related biologically, no current model explains both phenomena with a single biophysical mechanism. Most computational models describe sprouting at the level of the blood vessel, ignoring how cell behavior drives branch splitting during sprouting. We present a cell-based, Glazier–Graner–Hogeweg model (also called Cellular Potts Model) simulation of the initial patterning before the vascular cords form lumens, based on plausible behaviors of endothelial cells. The endothelial cells secrete a chemoattractant, which attracts other endothelial cells. As in the classic Keller–Segel model, chemotaxis by itself causes cells to aggregate into isolated clusters. However, including experimentally observed VE-cadherin–mediated contact inhibition of chemotaxis in the simulation causes randomly distributed cells to organize into networks and cell aggregates to sprout, reproducing aspects of both de novo and sprouting blood-vessel growth. We discuss two branching instabilities responsible for our results. Cells at the surfaces of cell clusters attempting to migrate to the centers of the clusters produce a buckling instability. In a model variant that eliminates the surface–normal force, a dissipative mechanism drives sprouting, with the secreted chemical acting both as a chemoattractant and as an inhibitor of pseudopod extension. Both mechanisms would also apply if force transmission through the extracellular matrix rather than chemical signaling mediated cell–cell interactions. The branching instabilities responsible for our results, which result from contact inhibition of chemotaxis, are both generic developmental mechanisms and interesting examples of unusual patterning instabilities.

Multi-scale modeling of tissues using CompuCell3D.

The study of how cells interact to produce tissue development, homeostasis, or diseases was, until recently, almost purely experimental. Now, multi-cell computer simulation methods, ranging from relatively simple cellular automata to complex immersed-boundary and finite-element mechanistic models, allow in silico study of multi-cell phenomena at the tissue scale based on biologically observed cell behaviors and interactions such as movement, adhesion, growth, death, mitosis, secretion of chemicals, chemotaxis, etc. This tutorial introduces the lattice-based Glazier-Graner-Hogeweg (GGH) Monte Carlo multi-cell modeling and the open-source GGH-based CompuCell3D simulation environment that allows rapid and intuitive modeling and simulation of cellular and multi-cellular behaviors in the context of tissue formation and subsequent dynamics. We also present a walkthrough of four biological models and their associated simulations that demonstrate the capabilities of the GGH and CompuCell3D.

The kinetics of cellular patterns

Many materials, including soap froths, polycrystalline alloys, ceramics, lipid monolayers and garnet films, have structures composed of either two- or three-dimensional polygonal domains separated by well defined boundaries. Usually, the surface energy of these boundaries makes the pattern unstable, causing certain grains to shrink and eventually to disappear. Thus the pattern coarsens continuously unless other factors arrest the motion of the boundaries. The authors review recent theoretical, computational and experimental progress in their understanding of the asymptotic scaling laws that describe coarsening. In most cases the elementary expectation, that the mean grain radius scales with the square root of time, is confirmed. They pay particular attention to the history of the field, to understand why this elementary result has remained in doubt until now.

Quasi-periodicity and dynamical systems: An experimentalist's view

Current theoretical and experimental work on quasiperiodicity is reviewed in this tutorial. The concept of universality and its relevance to experiments on nonlinear multifrequency systems is discussed. The reduction of experimental data using Poincare sections and the mathematical properties of the one-dimensional circle map are considered. Various dynamical systems technique for determining scaling and multifractal properties as well as other more traditional methods of analysis, are presented. Experimental observations that would support or refute the one-dimensional circle map model are emphasized. Experimental results are summarized, with emphasis on forced Rayleigh-Benard convection and solid-state systems. Accomplishments and open problems of the dynamical systems theory of quasiperiodicity are outlined. >

Dynamical mechanisms for skeletal pattern formation in the vertebrate limb

We describe a ‘reactor–diffusion’ mechanism for precartilage condensation based on recent experiments on chondrogenesis in the early vertebrate limb and additional hypotheses. Cellular differentiation of mesenchymal cells into subtypes with different fibroblast growth factor (FGF) receptors occurs in the presence of spatio–temporal variations of FGFs and transforming growth factor–betas (TGF–βs). One class of differentiated cells produces elevated quantities of the extracellular matrix protein fibronectin, which initiates adhesion–mediated preskeletal mesenchymal condensation. The same class of cells also produces an FGF–dependent laterally acting inhibitor that keeps condensations from expanding beyond a critical size. We show that this ‘reactor–diffusion’ mechanism leads naturally to patterning consistent with skeletal form, and describe simulations of spatio–temporal distribution of these differentiated cell types and the TGF–β and inhibitor concentrations in the developing limb bud.

A Framework for Three-Dimensional Simulation of Morphogenesis

We present COMPUCELL3D, a software framework for three-dimensional simulation of morphogenesis in different organisms. COMPUCELL3D employs biologically relevant models for cell clustering, growth, and interaction with chemical fields. COMPUCELL3D uses design patterns for speed, efficient memory management, extensibility, and flexibility to allow an almost unlimited variety of simulations. We have verified COMPUCELL3D by building a model of growth and skeletal pattern formation in the avian (chicken) limb bud. Binaries and source code are available, along with documentation and input files for sample simulations, at http:// compucell.sourceforge.net.

On multiscale approaches to three-dimensional modelling of morphogenesis

In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular to those of tissues and organs. Our current implementation combines a modified discrete model from statistical mechanics, the Cellular Potts Model, with a continuum reaction–diffusion model and a state automaton with well-defined conditions for cell differentiation transitions to model genetic regulation. This environment allows us to rapidly and compactly create computational models of a class of complex-developmental phenomena. To illustrate model development, we simulate a simplified version of the formation of the skeletal pattern in a growing embryonic vertebrate limb.