A novel mathematical model of heterogeneous cell proliferation.

We present a novel mathematical model of heterogeneous cell proliferation where the total population consists of a subpopulation of slow-proliferating cells and a subpopulation of fast-proliferating cells. The model incorporates two cellular processes, asymmetric cell division and induced switching between proliferative states, which are important determinants for the heterogeneity of a cell population. As motivation for our model we provide experimental data that illustrate the induced-switching process. Our model consists of a system of two coupled delay differential equations with distributed time delays and the cell densities as functions of time. The distributed delays are bounded and allow for the choice of delay kernel. We analyse the model and prove the nonnegativity and boundedness of solutions, the existence and uniqueness of solutions, and the local stability characteristics of the equilibrium points. We find that the parameters for induced switching are bifurcation parameters and therefore determine the long-term behaviour of the model. Numerical simulations illustrate and support the theoretical findings, and demonstrate the primary importance of transient dynamics for understanding the evolution of many experimental cell populations.