Abstract
Lymphocytes have been described to perform different motility patterns such as Brownian random walks, persistent random walks, and Lévy walks. Depending on the conditions, such as confinement or the distribution of target cells, either Brownian or Lévy walks lead to more efficient interaction with the targets. The diversity of these motility patterns may be explained by an adaptive response to the surrounding extracellular matrix (ECM). Indeed, depending on the ECM composition, lymphocytes either display a floating motility without attaching to the ECM, or sliding and stepping motility with respectively continuous or discontinuous attachment to the ECM, or pivoting behaviour with sustained attachment to the ECM. Moreover, on the long term, lymphocytes either perform a persistent random walk or a Brownian-like movement depending on the ECM composition. How the ECM affects cell motility is still incompletely understood. Here, we integrate essential mechanistic details of the lymphocyte-matrix adhesions and lymphocyte intrinsic cytoskeletal induced cell propulsion into a Cellular Potts model (CPM). We show that the combination of de novo cell-matrix adhesion formation, adhesion growth and shrinkage, adhesion rupture, and feedback of adhesions onto cell propulsion recapitulates multiple lymphocyte behaviours, for different lymphocyte subsets and various substrates. With an increasing attachment area and increased adhesion strength, the cells' speed and persistence decreases. Additionally, the model predicts random walks with short-term persistent but long-term subdiffusive properties resulting in a pivoting type of motility. For small adhesion areas, the spatial distribution of adhesions emerges as a key factor influencing cell motility. Small adhesions at the front allow for more persistent motility than larger clusters at the back, despite a similar total adhesion area. In conclusion, we present an integrated framework to simulate the effects of ECM proteins on cell-matrix adhesion dynamics. The model reveals a sufficient set of principles explaining the plasticity of lymphocyte motility.
Highlights
Lymphocytes continuously patrol in tissues and are recruited to infected areas to detect and clear the area of pathogens and cancer cells
We present a model of lymphocyte motility driven by adhesions that grow, shrink and rupture in response to the extracellular matrix (ECM) and cellular forces
Our model suggests that cell motility is affected by the force required to break adhesions and the rate at which new adhesions form
Summary
Lymphocytes continuously patrol in tissues and are recruited to infected areas to detect and clear the area of pathogens and cancer cells. Theoretical studies have shown that the efficiency by which active particles, such as motile cells, can find target particles depends on the characteristics of the trajectories that lymphocytes follow, the local density of the environment, and the distribution of targets. Relative to Brownian walks, subdiffusive random walks are characterized by enhanced local exploration This enhances the probability that the active particle binds the target within a given time [5], suggesting that this strategy becomes effective when the lymphocyte has detected its target, e.g., through detection of diffusive signals, but is still unable to bind it, or when the lymphocyte needs to hit the target multiple times for an effective kill of the target [6]. For a recent in-depth study of search efficiencies of subdiffusive, diffusive and superdiffusive random walkers, we refer to Ref. [7]
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