Mathematical and numerical modelling of cell migration

Abstract : Collective or individual cell displacements are essential in fundamental physiological processes (immune response, embryogenesis) as well as in pathological developments (tumor metastasis). The intracellular processes responsible for cell motion have a complex self-organized activity spanning different time and space scales. Highlighting general principles of migration is therefore a challenging task.In a first part, we build stochastic particular models of migration. To do so, we describe key intracellular processes as discrete in space by using stochastic population models. Then, by a renormalization in large population, infinitesimal size and accelerated dynamics, we obtain continuous stochastic equations for the dynamics of interest, allowing a relation between the intracellular dynamics and the macroscopic displacement.First, we study the case of a leukocyte carried by the blood flow and developing adhesive bonds with the artery wall, until an eventual stop. The binding dynamics is described by a stochastic Birth and Death with Immigration process. These bonds correspond to resistive forces to the motion. We obtain explicitly the mean stopping time of the cell.Then, we study the case of cell crawling, that happens by the formation of protrusions on the cell edge, that grow on the substrate and exert traction forces. We describe this dynamics by a structured population process, where the structure comes from the protrusions' orientations. The limiting continuous model can be analytically studied in the 1D migration case, and gives rise to a Fokker-Planck equation on the probability distribution for the protrusion density. For a stationary profile, we can show the existence of a dichotomy between a non motile state and a directional displacement state.In a second part, we build a deterministic minimal migration model in a discoïdal cell domain. We base our work on the idea such that the structures responsible for migration also reinforce cell polarisation, which favors in return a directional displacement. This positive feedback loop involves the convection of a molecular marker, whose inhomogeneous spatial repartition is characteristic of a polarised state.The model writes as a convection-diffusion problem for the marker's concentration, where the advection field is the velocity field of the Darcy fluid that describes the cytoskeleton. Its active character is carried by boundary terms, which makes the originality of the model.From the analytical point of vue, the 1D model shows a dichotomy depending on a critical mass for the marker. In the subcritical and critical cases, it is possible to show global existence of weak solutions, as well as a rate-explicit convergence of the solution towards the unique stationary profile, corresponding to a non-motile state. Above the critical mass, for intermediate values, we show the existence of two additional stationary solutions corresponding to polarised motile profiles. Moreover, for asymmetric enough initial profiles, we show the finite time apparition of a blowup.Studying a more complex model involving activation of the marker at the cell membrane permits to get rid of this singularity.From the numerical point of vue, numerical experiments are led in 2D either in finite volumes (Matlab) or finite elements (FreeFem++) discretizations. They allow to show both motile and non motile profiles. The effect of stochastic fluctuations in time and space are studied, leading to numerical simulations of cases of responses to an external signal, either chemical (chemotaxis) or mechanical (obstacles).
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Christèle Etchegaray. Mathematical and numerical modelling of cell migration. Analysis of PDEs [math.AP]. Université Paris-Saclay, 2016. English. ⟨NNT : 2016SACLS428⟩. ⟨tel-01533458⟩



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