Mathematical models of physiologically structured cell populations

Laburpena

In this thesis we will consider a nonlinear cell population model where cells are structured with respect to the content of cyclin and CDK. This model leads to a first order nonlinear partial differential equations system with non local terms. To study this system we will use the theory of positive linear semigroups and the semilinear formulation, which are very powerful tools to deal with the analysis of this kind of models, both from the point of view of the initial value problem as well as the existence and stability of steady states. The model considered in the thesis describes the following biological situation: the cells are structured with respect to the content of a certain group of proteins called cyclin and CDK and they are divided the cells into two types: proliferating and quiescent cells. The proliferating cells grow and divide, giving birth at the end of the cell cycle to new cells, or else transit to the quiescent compartment, whereas quiescent cells do not age nor divide nor change their cyclin content but either transit back to the proliferating compartment or else stay in the quiescent compartment. Moreover, both proliferating and quiescent cells may experiment apoptosis, i.e. programmed cell death. The only nonlinear term is a recruitment term of quiescent cells going back to the proliferating phase. In this work we start proving global existence, uniqueness and positiveness of the solutions of the initial value problem. We rewrite our system in an abstract form and show that some linear operator is the infinitesimal generator of a positive C0 semigroup. On the other hand we use the standard semilinear formulation for the nonlinear (abstract) equation and obtain a unique global positive solution for any positive initial condition in L1. We also prove the existence and uniqueness of a nontrivial steady state of our system under suitable hypotheses. As it is often done in similar situations, the problem is related to proving the existence (and uniqueness) of a positive normalized eigenvector. This eigenvector corresponds to the dominant eigenvalue of a certain positive linear operator parameterized by the value of the (one dimensional) feedback variable G. The existence of both dominant eigenvalue and (unique) positive eigenvector is given by a version of the infinite dimensional Perron-Frobenius theorem. We include numerical simulations based on the integration along the characteristic lines. With the help of these numerical simulations we find instability of the steady state for parameter values compatible with the ones which give instability in the finite dimensional model. We also include a computation showing the existence of cyclin-independent solutions for a very particular choice of the parameter values and functions defining the model. Finally we use the so-called cumulative or delayed formulation of the structured population dynamics. In particular we have considered a different version of the model studied before, where one assumes that proliferating cells can become quiescent only once opposed to the other approach where these transitions can occur infinitely many times and moreover, we also assume that there is a particular value x of the cyclin content that separates cells which still cannot divide from the others which are able to divide. The model equation turns out to be a delay equation relating the current values of these variables with their history (their value in the past). Using this, one can prove existence and uniqueness of solutions of the initial value problem, and the linear stability principle by means of a semi-linear formulation in the framework of dual semigroups.