Cortical Factor Feedback Model for Cellular Locomotion and Cytofission

Eukaryotic cells can move spontaneously without being guided by external cues. For such spontaneous movements, a variety of different modes have been observed, including the amoeboid-like locomotion with protrusion of multiple pseudopods, the keratocyte-like locomotion with a widely spread lamellipodium, cell division with two daughter cells crawling in opposite directions, and fragmentations of a cell to multiple pieces. Mutagenesis studies have revealed that cells exhibit these modes depending on which genes are deficient, suggesting that seemingly different modes are the manifestation of a common mechanism to regulate cell motion. In this paper, we propose a hypothesis that the positive feedback mechanism working through the inhomogeneous distribution of regulatory proteins underlies this variety of cell locomotion and cytofission. In this hypothesis, a set of regulatory proteins, which we call cortical factors, suppress actin polymerization. These suppressing factors are diluted at the extending front and accumulated at the retracting rear of cell, which establishes a cellular polarity and enhances the cell motility, leading to the further accumulation of cortical factors at the rear. Stochastic simulation of cell movement shows that the positive feedback mechanism of cortical factors stabilizes or destabilizes modes of movement and determines the cell migration pattern. The model predicts that the pattern is selected by changing the rate of formation of the actin-filament network or the threshold to initiate the network formation

Multiscale modelling of vascular tumour growth in 3D: the roles of domain size & boundary condition

We investigate a three-dimensional multiscale model of vascular tumour growth, which couples blood flow, angiogenesis, vascular remodelling, nutrient/growth factor transport, movement of, and interactions between, normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. In particular, we determine how the domain size, aspect ratio and initial vascular network influence the tumour's growth dynamics and its long-time composition. We establish whether it is possible to extrapolate simulation results obtained for small domains to larger ones, by constructing a large simulation domain from a number of identical subdomains, each subsystem initially comprising two parallel parent vessels, with associated cells and diffusible substances. We find that the subsystem is not representative of the full domain and conclude that, for this initial vessel geometry, interactions between adjacent subsystems contribute to the overall growth dynamics. We then show that extrapolation of results from a small subdomain to a larger domain can only be made if the subdomain is sufficiently large and is initialised with a sufficiently complex vascular network. Motivated by these results, we perform simulations to investigate the tumour's response to therapy and show that the probability of tumour elimination in a larger domain can be extrapolated from simulation results on a smaller domain. Finally, we demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

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. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Robustness Analysis and Behavior Discrimination in Enzymatic Reaction Networks

Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodology involving sensitivity analysis is conducted to determine bifurcation thresholds for a limited number of model parameters or initial conditions. In a second step, this boundary detection is supplemented by a global robustness analysis, based on quasi-Monte Carlo approach that takes into account all model parameters. We apply this method to a well-documented enzymatic reaction network describing collagen proteolysis by matrix metalloproteinase MMP2 and membrane type 1 metalloproteinase (MT1-MMP) in the presence of tissue inhibitor of metalloproteinase TIMP2. For this model, our method provides an extended analysis and quantification of network robustness toward paradoxical TIMP2 switching activity between activation or inhibition of MMP2 production. Further implication of our approach is illustrated by demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams that specify key parameters values controlling the co-existence of stable steady and non-steady oscillatory proteolytic dynamics

Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment

Hybrid Modelling in Biology: a Classification Review

International audienceThis paper presents a general review on hybrid modelling which is about to become ubiquitous in biological and medical modelling. Hybrid modelling is classically defined as the coupling of a continuous approach with a discrete one, in order to model a complex phenomenon that cannot be described in a standard homogeneous way mainly due to its inherent multiscale nature. In fact, hybrid modelling can be more than that since any types of coupled formalisms qualify as being hybrid. This review first presents the evolution and current context of this modelling approach. It then proposes a classification of the models through three different types that relate to the nature and level of coupling of the formalisms used

A Hybrid Model to Test the Importance of Mechanical Cues Driving Cell Migration in Angiogenesis

International audienceMany studies are stressing the crucial importance of the mechanical component in angiogenesis, but still, very few models really integrate mechanics. In this paper, we propose to investigate the importance of mechanical cues for cell migration in the context of angiogenesis. We propose a hybrid continuous-discrete model that describes the individual migration of contracting cells on an elastic matrix of fibres. The matrix is described as a continuum whereas the cells are described as discrete elements. We also take into account the degradation of the matrix by proteases. The Young's modulus characterizing the matrix rigidity depends on the local and time-dependent density of matrix fibres. Our results show that acting on the mechanics,specifically on the cell traction force intensity and on the matrix rigidity, can significantly alter cell migration and angiogenesis. First, there is a limited range of traction force intensities for which a vascular network can be obtained. Second, the matrix rigidity plays a role, but only in a very specific range, compatible with the underlying biological process. Alteration of the matrix due to cell degradation appears too small to induce significant changes in cell migration trajectories

Training Needs analysis: a useful tool for planning staff development

In this paper, we present a theoretical investigation of the influence of blood flow through a tumour-induced capillary network, whereby the vascular architecture adapts as it grows to the associated haemodynamic forces resulting in what we describe as adaptive tumour-induced angiogenesis (ATIA). The network is generated in response to tumour angiogenic factors (TAFs), which are released from hypoxic cells within a solid tumour. We first describe a refined model for tumour-induced angiogenesis, which aims to describe the capillary growth process at the cellular level by explicitly taking into account the effects of matrix degrading enzymes and the local properties of the host tissue during endothelial cell migration. We then incorporate blood rheological properties into the formulation and investigate the influence of wall shear stress induced by the blood flow during dynamic vascular growth. We then go on to examine a number of feedback mechanisms affecting vascular resistance and network architecture. The mechanisms considered include those proposed by Pries and co-workers [A.R. Pries, T.W. Secomb, P. Gaehtgens, Structural adaptation and stability of microvascular networks: theory and simulation, Am. J. Physiol. Heart Circ. Physiol. 44 (1998) H349?H360; A.R. Pries, B. Reglin, T.W. Secomb, Structural adaptation of microvascular networks: functional roles of adaptative responses, Am. J. Physiol. Heart Circ. Physiol. 281 (2001) H1015?H1025; A.R. Pries, B. Reglin, T.W. Secomb, Structural adaptation of microvascular networks: roles of the pressure response, Hypertension 38 (2001) 1476?1479] and both haemodynamic (non-linear viscosity) and metabolic constraints are taken into account. Subsequent simulations of chemotherapeutic drug perfusion through the system show that vascular adaptation leads to a significant benefit in treatment delivery to the tumour. The results clearly demonstrate that the combined effects of network architecture and vessel compliance should be included in future models of angiogenesis if therapy protocols and treatment efficacy are to be adequately assessed