Diffusion-driven instabilities and emerging spatial patterns in patchy landscapes

Spatial variation in population densities across a landscape is a feature of many ecological systems, from self-organised patterns on mussel beds to spatially restricted insect outbreaks. It occurs as a result of environmental variation in abiotic factors and/or biotic factors structuring the spatial distribution of populations. However the ways in which abiotic and biotic factors interact to determine the existence and nature of spatial patterns in population density remain poorly understood. Here we present a new approach to studying this question by analysing a predator–prey patch-model in a heterogenous landscape. We use analytical and numerical methods originally developed for studying nearest- neighbour (juxtacrine) signalling in epithelia to explore whether and under which conditions patterns emerge. We find that abiotic and biotic factors interact to promote pattern formation. In fact, we find a rich and highly complex array of coexisting stable patterns, located within an enormous number of unstable patterns. Our simulation results indicate that many of the stable patterns have appreciable basins of attraction, making them significant in applications. We are able to identify mechanisms for these patterns based on the classical ideas of long-range inhibition and short-range activation, whereby landscape heterogeneity can modulate the spatial scales at which these processes operate to structure the populations

Phase differences in reaction-diffusion-advection systems and applications to morphogenesis

The authors study the effect of advection on reaction-diffusion patterns. It is shown that the addition of advection to a two-variable reaction–diffusion system with periodic boundary conditions results in the appearance of a phase difference between the patterns of the two variables which depends on the difference between the advection coefficients. The spatial patterns move like a travelling wave with a fixed velocity which depends on the sum of the advection coefficients. By a suitable choice of advection coefficients, the solution can be made stationary in time. In the presence of advection a continuous change in the diffusion coefficients can result in two Turing-type bifurcations as the diffusion ratio is varied, and such a bifurcation can occur even when the inhibitor species does not diffuse. It is also shown that the initial mode of bifurcation for a given domain size depends on both the advection and diffusion coefficients. These phenomena are demonstrated in the numerical solution of a particular reaction–diffusion system, and finally a possible application of the results to pattern formation in Drosophila larvae is discussed

Mathematical models for cell-matrix interactions during dermal wound healing

This paper contains a review of our recent work on the mathematical modeling of cell interaction with extracellular matrix components during the process of dermal wound healing. The models are of partial differential equation type and allow us to investigate in detail how various mechanochemical effects may be responsible for certain wound healing disorders such as fibrocontractive and fibroproliferative diseases. We also present a model for wound healing angiogenesis. The latter has several features in common with angiogenesis during cancer tumour growth and spread so a deeper understanding of the phenomenon in the context of wound healing may also help in the treatment of certain cancers

Cellular pattern formation during Dictyostelium aggregation

The development of multicellularity in the life cycle of Dictyostelium discoideum provides a paradigm model system for biological pattern formation. Previously, mathematical models have shown how a collective pattern of cell communication by waves of the messenger molecule cyclic adenosine 3′5′-monophosphate (cAMP) arises from excitable local cAMP kinetics and cAMP diffusion. Here we derive a model of the actual cell aggregation process by considering the chemotactic cell response to cAMP and its interplay with the cAMP dynamics. Cell density, which previously has been treated as a spatially homogeneous parameter, is a crucial variable of the aggregation model. We find that the coupled dynamics of cell chemotaxis and cAMP reaction-diffusion lead to the break-up of the initially uniform cell layer and to the formation of the striking cell stream morphology which characterizes the aggregation process in situ. By a combination of stability analysis and two-dimensional simulations of the model equations, we show cell streaming to be the consequence of the growth of a small-amplitude pattern in cell density forced by the large-amplitude cAMP waves, thus representing a novel scenario of spatial patterning in a cell chemotaxis system. The instability mechanism is further analysed by means of an analytic caricature of the model, and the condition for chemotaxis-driven instability is found to be very similar to the one obtained for the standard (non-oscillatory) Keller-Segel system. The growing cell stream pattern feeds back into the cAMP dynamics, which can explain in some detail experimental observations on the time evolution of the cAMP wave pattern, and suggests the characterization of the Dictyostelium aggregation field as a self-organized excitable medium

A Mathematical Model for Lymphangiogenesis in Normal and Diabetic Wounds

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis) very few have been proposed for the regeneration of the lymphatic network. Moreover, lymphangiogenesis is markedly distinct from angiogenesis, occurring at different times and in a different manner. Here a model of five ordinary differential equations is presented to describe the formation of lymphatic capillaries following a skin wound. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from experimental and clinical data. The system is then solved numerically and the results are compared with the available biological literature. Finally, a parameter sensitivity analysis of the model is taken as a starting point for suggesting new therapeutic approaches targeting the enhancement of lymphangiogenesis in diabetic wounds. The work provides a deeper understanding of the phenomenon in question, clarifying the main factors involved. In particular, the balance between TGF-$\beta$ and VEGF levels, rather than their absolute values, is identified as crucial to effective lymphangiogenesis. In addition, the results indicate lowering the macrophage-mediated activation of TGF-$\beta$ and increasing the basal lymphatic endothelial cell growth rate, \emph{inter alia}, as potential treatments. It is hoped the findings of this paper may be considered in the development of future experiments investigating novel lymphangiogenic therapies

Pattern formation in reaction diffusion models with spatially inhomogeneous diffusion coefficients

Reaction-diffusion models for biological pattern formation have been studied extensively in a variety of embryonic and ecological contexts. However, despite experimental evidence pointing to the existence of spatial inhomogeneities in various biological systems, most models have only been considered in a spatially homogeneous environment. The authors consider a two-chemical reaction-diffusion mechanism in one space dimension in which one of the diffusion coefficients depends explicitly on the spatial variable. The model is analysed in the case of a step function diffusion coefficient and the insight gained for this special case is used to discuss pattern generation for smoothly varying diffusion coefficients. The results show that spatial inhomogeneity may be an important biological pattern regulator, and possible applications of the model to chondrogenesis in the vertebrate limb are suggested

Unravelling the Turing bifurcation using spatially varying diffusion coefficients

The Turing bifurcation is the basic bifurcation generating spatial pattern, and lies at the heart of almost all mathematical models for patterning in biology and chemistry. In this paper the authors determine the structure of this bifurcation for two coupled reaction diffusion equations on a two-dimensional square spatial domain when the diffusion coefficients have a small explicit variation in space across the domain. In the case of homogeneous diffusivities, the Turing bifurcation is highly degenerate. Using a two variable perturbation method, the authors show that the small explicit spatial inhomogeneity splits the bifurcation into two separate primary and two separate secondary bifurcations, with all solution branches distinct. This splitting of the bifurcation is more effective than that given by making the domain slightly rectangular, and shows clearly the structure of the Turing bifurcation and the way in which the! var ious solution branches collapse together as the spatial variation is reduced. The authors determine the stability of the solution branches, which indicates that several new phenomena are introduced by the spatial variation, including stable subcritical striped patterns, and the possibility that stable stripes lose stability supercritically to give stable spotted patterns

Modelling the effects of Transforming Growth Factor-β on extracellular matrix alignment in dermal wound repair

We present a novel mathematical model for collagen deposition and alignment during dermal wound healing, focusing on the regulatory effects of transforming growth factor-β (TGFβ.) Our work extends a previously developed model which considers the interactions between fibroblasts and an extracellular matrix composed of collagen and a fibrin based blood clot, by allowing fibroblasts to orient the collagen matrix, and produce and degrade the extracellular matrix, while the matrix directs the fibroblasts and control their speed. Here we extend the model by allowing a time varying concentration of TGFβ to alter the properties of the fibroblasts. Thus we are able to simulate experiments which alter the TGFβ profile. Within this model framework we find that most of the known effects of TGFβ, i.e., changes in cell motility, cell proliferation and collagen production, are of minor importance to matrix alignment and cannot explain the anti-scarring properties of TGFβ. However, we find that by changing fibroblast reorientation rates, consistent with experimental evidence, the alignment of the regenerated tissue can be significantly altered. These data provide an explanation for the experimentally observed influence of TGFβ on scarring

A multiscale model for collagen alignment in wound healing

It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring