Computational modelling of cell motility modes emerging from cell-matrix adhesion dynamics

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 motion without attaching to the ECM, or sliding and stepping motion 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 \textit{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 can predict short-term persistent with long-term subdiffusive motility, showing a pivoting motion. For small adhesion areas, we observe that the spatial distribution of adhesions influences cell motility. Small adhesions at the front allow for more persistent motion 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.

Modelling the mechanical cross-talk between cells and fibrous extracellular matrix using hybrid cellular Potts and molecular dynamics methods

“…Although the contractile cell could also be represented entirely using the molecular dynamics model (HOOMD-blue), e.g., by using the subcellular element approach [Newman, 2005, Sandersius and Newman, 2008], our hybrid approach will show its strength particularly in more complex problems. The hybrid approach can benefit from an enormous ‘library’ of available extensions of the CPM for modelling complex cell behavior ranging from chemotaxis [Savill and Hogeweg, 1997] and anomalous cell migration [Niculescu et al, 2015, Van Steijn et al, 2022], to complex multicellular developmental mechanisms such as angiogenesis [Van Oers et al, 2014] and somitogenesis [Hester et al, 2011, Nelemans et al, 2020]. Network structure likely plays a prominent role in such complex cell behavior.…”

“…Additional terms inspired by biophysical observations, such as cell surface tension, enable the CPM to accurately predict cell spreading on adhesive substrates, focal adhesion formation, and the stresses generated by cell forces on the ECM [Albert and Schwarz, 2014, Rens and Merks, 2017, 2020, Van Oers et al, 2014]. The framework is amenable to extensions, for example to include force generation and cell shape changes induced by the actin cytoskeleton dynamics [Marée et al, 2006, Niculescu et al, 2015, Schakenraad et al, 2022, Van Steijn et al, 2022]. These features have made the CPM a popular tool to study the emergence of biophysical properties at the cell and tissue scale from simple (sub-)cellular rules [Albert and Schwarz, 2014, Rens and Merks, 2020, Wortel et al, 2021].…”

Constraints and trade-offs shape the evolution of T cell search strategies

“…Would they adopt a different pattern in the same environment when fighting a more prevalent pathogen, or would they maintain the same migration mode even when it is no longer beneficial? We therefore suggest using models like the CPM [31, 13, 39, 40], where migration patterns arise naturally from an interaction between the cell and its environment rather than being imposed, to define the baseline expectations for T-cell search. By investigating which migratory characteristics emerge without being optimal or even beneficial, we can zoom in on the motility aspects that have truly been evolved to assist immune system function—without being misled by features that are merely inevitable side effects of an intracellular machinery acting in a complex environment.…”

Cellular Tango: how extracellular matrix adhesion choreographs Rac-Rho signaling and cell movement

“…Our current adhesion model does not consider merging of clusters or local differences in free integrins, nor do we model integrin diffusion across the cell membrane. See [78] for a discrete adhesion model with spatial growth, merging and shrinkage of adhesion patches. There, a coarse grained simplified adhesion model in combination with phenomenological actin dynamics [79] in a CPM was used to reproduce multiple migration modes in lymphocytes.…”