The aim of this study was to describe and analyze the regulation and spatio-temporaldynamics of melanocyte migration in vitro and its coupling to celldivision and interaction with the matrix. The melanocyte lineage is particularlyinteresting because it is involved in both embryonic development andoncogenesis/metastasis (melanoma). Biological experiments were performed on two melanocytecell lines established from wild-type and β-catenin-transgenic mice(bcat*). The multi-functional β-catenin molecule is known to be able toregulate the transcription of various genes involved in cell proliferation and migration,particularly in the melanocyte lineage. We also investigated fibronectin, anextra-cellular matrix protein that binds integrins, thereby providing adhesion points forcells and encouraging migration. As the migration of individual cells were followed,automated methods were required for processing the large amount of data generated by thetime-lapse video-microscopy. A model-based approach for automated cell tracking wasevaluated on a sample by comparison with manual tracking. This method was found reliablein studying overall cell behaviour. Its application to all the observed sequences providedinsight into the factors affecting melanocyte migration in vitro:melanocytes of mutated form of β-catenin showed higher division rates andno contact inhibition of growth was induced by the resulting increase in cell density.However, cell density limited the amplitude of cell displacements, although their motilitywas less affected. The high fibronectin concentration bound to substratum promoted cellmigration and motility, the effect being more intense for wild-type cells than for cellswith β-catenin over-expression. During the division process, cellmigration speed increased rapidly then decreased slowly. Analyses of such data is expectedto lead both to biological answers and to a framework for a better modeling processes inthe future.

Cell motility is an integral part of a diverse set of biological processes. The quest formathematical models of cell motility has prompted the development of automated approachesfor gathering quantitative data on cell morphology, and the distribution of molecularplayers involved in cell motility. Here we review recent approaches for quantifying cellmotility, including automated cell segmentation and tracking. Secondly, we present our ownnovel method for tracking cell boundaries of moving cells, the Electrostatic ContourMigration Method (ECMM), as an alternative to the generally accepted level set method(LSM). ECMM smoothly tracks regions of the cell boundary over time to compute localmembrane displacements using the simple underlying concept of electrostatics. It offerssubstantial speed increases and reduced computational overheads in comparison to the LSM.We conclude with general considerations regarding boundary tracking in the context ofmathematical modelling.

In this paper, we propose a computational model to investigate the coupling between cell’s adhesions and actin fibres and how this coupling affects cell shape and stability. To accomplish that, we take into account the successive stages of adhesion maturation from adhesion precursors to focal complexes and ultimately to focal adhesions, as well as the actin fibres evolution from growing filaments, to bundles and finally contractile stress fibres.

We use substrates with discrete patterns of adhesive patches, whose inter-patches distance can be modulated in order to control the location of the adhesions and the resulting fibres architecture. We then investigate the emergence of stable cell morphologies as a function of the inter-patches distance, for two different cell phenotypes generated from the model. Force generated by the stress fibres on the focal adhesions and specifically the influence of the cell contractility are also investigated.

Our results suggest that adhesion lifetime and fibre growing rate are the key parameters in the emergence of stable cell morphologies and the limiting factors for the magnitude of the mean tension force from the fibres on the focal adhesions.

We present a simple mechanism of cell motility in a confined geometry, inspired by recentmotility assays in microfabricated channels. This mechanism relies mainly on the couplingof actin polymerisation at the cell membrane to geometric confinement. We first showanalytically using a minimal model of polymerising viscoelastic gel confined in a narrowchannel that spontaneous motion occurs due to polymerisation alone. Interestingly, thismechanism does not require specific adhesion with the channel walls, and yields velocitiespotentially larger than the polymerisation velocity of the gel. We then study the effectof the contractile activity of myosin motors, and show that whilst it is not necessary toinduce motion, it quantitatively increases the velocity of motion in the polymerisationmechanism we describe. Our model qualitatively accounts for recent experiments which showthat cells without specific adhesion proteins are motile only in confined environmentswhile they are unable to move on a flat surface. It also constitutes a first step in thestudy of cell migration in more complex confined geometries such as living tissues.

Collective cell motility and its guidance via cell-cell contacts is instrumental in several morphogenetic and pathological processes such as vasculogenesis or tumor growth. Multicellular sprout elongation, one of the simplest cases of collective motility, depends on a continuous supply of cells streaming along the sprout towards its tip. The phenomenon is often explained as leader cells pulling the rest of the sprout forward via cell-cell adhesion. Building on an empirically demonstrated analogy between surface tension and cell-cell adhesion, we demonstrate that such a mechanism is unable to recruit cells to the sprout. Moreover, the expansion of such hypothetical sprouts is limited by a form of the Plateau-Taylor instability. In contrast, actively moving cells – guided by cell-cell contacts – can readily populate and expand linear sprouts. We argue that preferential attraction to the surfaces of elongated cells can provide a generic mechanism, shared by several cell types, for multicellular sprout formation.

The oriented movement of biological cells or organisms in response to a chemical gradientis called chemotaxis. The most interesting situation related to self-organizationphenomenon takes place when the cells detect and response to a chemical which is secretedby themselves. Since pioneering works of Patlak (1953) and Keller and Segel (1970) manyparticularized models have been proposed to describe the aggregation phase of thisprocess. Most of efforts were concentrated, so far, on mathematical models in which theformation of aggregate is interpreted as finite time blow-up of cell density. In recentlyproposed models cells are no more treated as point masses and their finite volume isaccounted for. Thus, arbitrary high cell densities are precluded in such description and athreshold value for cells density is a priori assumed. Different modelingapproaches based on this assumption lead to a class of quasilinear parabolic systems withstrong nonlinearities including degenerate or singular diffusion. We give a survey ofanalytical results on the existence and uniqueness of global-in-time solutions, theirconvergence to stationary states and on a possibility of reaching the density threshold bya solution. Unsolved problems are pointed as well.

Bacillus subtilis swarms rapidly over the surface of a synthetic mediumcreating remarkable hyperbranched dendritic communities. Models to reproduce such effectshave been proposed under the form of parabolic Partial Differential Equations representingthe dynamics of the active cells (both motile and multiplying), the passive cells(non-motile and non-growing) and nutrient concentration. We test the numerical behavior ofsuch models and compare them to relevant experimental data together with a criticalanalysis of the validity of the models based on recent observations of the swarmingbacteria which show that nutrients are not limitating but distinct subpopulations growingat different rates are likely present.

Over the past decade or so, there have been a large number of modelling approaches aimedat elucidating the most important mechanisms affecting the formation of new capillariesfrom parent blood vessels — a process known as angiogenesis. Most studies have focussedupon the way in which capillary sprouts are initiated and migrate in response todiffusible chemical stimuli supplied by hypoxic stromal cells and leukocytes in thecontexts of solid tumour growth and wound healing. However, relatively few studies haveexamined the important role played by blood perfusion during angiogenesis and fewer stillhave explored the ways in which a dynamically evolving vascular bed architecture canaffect the distribution of flow within it. From the perspective of solid tumour growthand, perhaps more importantly, its treatment (e.g. chemotherapy), it would clearly be ofsome benefit to understand this coupling between vascular structure and perfusion morefully. This paper focuses on the implications of such a coupling upon chemotherapeutic,anti-angiogenic, and anti-vascular treatments.

In an extension to previous work by the authors, the issue of pericyte recruitment duringvessel maturation is considered in order to study the effects of different anti-vascularand anti-angiogenic therapies from a more rigorous modelling standpoint. Pericytes are aprime target for new vascular disrupting agents (VDAs) currently in clinical trials.However, different compounds attack different components of the vascular network and theimplications of targeting only certain elements of the capillary bed are not immediatelyclear. In light of these uncertainties, the effects of anti-angiogenic and anti-vasculardrugs are re-examined by using an extended model that includes an interdependency betweenvessel remodelling potential and local pericyte density. Two- and three-dimensionalsimulation results are presented and suggest that it may be possible to identify aVDA-specific “plasticity window” (a time period corresponding to low pericyte density),within which a given VDA would be most effective.

In vitro transmesothelial migration assays of ovarian cancer cells, isolated oraggregated in multicellular spheroids, are reproduced deducing suitable Cellular PottsModels (CPM). We show that the simulations are in good agreement with the experimentalevidence and that the overall process is regulated by the activity of matrixmetalloproteinases (MMPs) and by the interplay of the adhesive properties of the cellswith the extracellular matrix and between cells, both of the same type and of differenttypes. In particular, the process depends on the ability of the cell to induce theloosening of cadherin-mediated junctions. Coherently with experiments, it is found thatsingle cell invasion is more conservative with a crucial role played by MMPs. A similarimportant role is played in cell spheroid invasion, which in comparison is moredisruptive. It achieves monofocal or multifocal characteristics according to the relativeadhesion affinity among cells or between them and the mesothelial layer.

In this article a novel model framework to simulate cells and their internal structure is described. The model is agent-based and suitable to simulate single cells with a detailed internal structure as well as multi-cellular compounds. Cells are simulated as a set of many interacting particles, with neighborhood relations defined via a Delaunay triangulation. The interacting sub-particles of a cell can assume specific roles – i.e., membrane sub-particle, internal sub-particle, organelles, etc –, distinguished by specific interaction potentials and, eventually, also by the use of modified interaction criteria. For example, membrane sub-particles may interact only on a two-dimensional surface embedded on three-dimensional space, described via a restricted Delaunay triangulation. The model can be used not only to study cell shape and movement, but also has the potential to investigate the coupling between internal space-resolved movement of molecules and determined cell behaviors.