Abstract
Moving fronts of cells are essential for development, repair and disease progression. Therefore, understanding and quantifying the details of the mechanisms that drive the movement of cell fronts is of wide interest. Quantitatively identifying the role of intercellular interactions, and in particular the role of cell pushing, remains an open question. In this work, we report a combined experimental-modelling approach showing that intercellular interactions contribute significantly to the spatial spreading of a population of cells. We use a novel experimental data set with PC-3 prostate cancer cells that have been pretreated with Mitomycin-C to suppress proliferation. This allows us to experimentally separate the effects of cell migration from cell proliferation, thereby enabling us to focus on the migration process in detail as the population of cells recolonizes an initially-vacant region in a series of two-dimensional experiments. We quantitatively model the experiments using a stochastic modelling framework, based on Langevin dynamics, which explicitly incorporates random motility and various intercellular forces including: (i) long range attraction (adhesion); and (ii) finite size effects that drive short range repulsion (pushing). Quantitatively comparing the ability of this model to describe the experimentally observed population-level behaviour provides us with quantitative insight into the roles of random motility and intercellular interactions. To quantify the mechanisms at play, we calibrate the stochastic model to match experimental cell density profiles to obtain estimates of cell diffusivity, D, and the amplitude of intercellular forces, f0. Our analysis shows that taking a standard modelling approach which ignores intercellular forces provides a poor match to the experimental data whereas incorporating intercellular forces, including short-range pushing and longer range attraction, leads to a faithful representation of the experimental observations. These results demonstrate a significant role of cell pushing during cell front movement and invasion.
Highlights
Moving cell fronts occur during many physiological processes, such as wound healing, morphogenesis, and malignant invasion [1,2,3,4]
We introduce the discrete mathematical model which accounts for random motility and intercellular interactions, including short range pushing and longer range attraction, as well as incorporating a mechanism for describing dynamic cell size changes
Results in figure 14 compares discrete density profiles obtained using Model IV parameterized with the best-fit estimate D = 700 μm2 h−1 where we see no improvement in the quality of match between the calibrated mathematical model and the experimental data relative to Model 1
Summary
Moving cell fronts occur during many physiological processes, such as wound healing, morphogenesis, and malignant invasion [1,2,3,4]. Cell fronts are observed as advancing, sharp boundaries between densely occupied and vacant regions, or as a moving interface between two distinct populations of cells [5]. An advancing interface between two populations of cells is often associated with malignant invasion into surrounding tissues [8, 9]. Improving our understanding of how cell populations spread can provide important, clinically-relevant information about the nature of moving cell fronts. Moving cell fronts have been studied, both in vitro and in vivo, to provide both qualitative and quantitative information about the mechanisms that drive front movement. A fundamental question, which remains largely overlooked in the mathematical biology literature, is what is the role of cell-to-cell pushing and how does it influence population-level front movement?
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