Excitable dynamics in a molecularly-explicit model of cell motility: Mixed-mode oscillations and beyond.

Mesenchymal cell motility is mainly regulated by two members of the Rho-family of GTPases, called Rac and Rho. The mutual inhibition exerted by these two proteins on each other's activation and the promotion of Rac activation by an adaptor protein called paxillin have been implicated in driving cellular polarization comprised of front (high active Rac) and back (high active Rho) during cell migration. Mathematical modeling of this regulatory network has previously shown that bistability is responsible for generating a spatiotemporal pattern underscoring cellular polarity called wave-pinning when diffusion is included. We previously developed a 6V reaction-diffusion model of this network to decipher the role of Rac, Rho and paxillin (along with other auxiliary proteins) in generating wave-pinning. In this study, we simplify this model through a series of steps into an excitable 3V ODE model comprised of one fast variable (the scaled concentration of active Rac), one slow variable (the maximum paxillin phosphorylation rate - turned into a variable) and a very slow variable (a recovery rate - also turned into a variable). We then explore, through slow-fast analysis, how excitability is manifested by showing that the model can exhibit relaxation oscillations (ROs) as well as mixed-mode oscillations (MMOs) whose underlying dynamics are consistent with a delayed Hopf bifurcation with a canard explosion. By reintroducing diffusion and the scaled concentration of inactive Rac into the model, we obtain a 4V PDE model that generates several unique spatiotemporal patterns that are relevant to cell motility. These patterns are then characterized and their impact on cell motility are explored by employing the cellular potts model (CPM). Our results reveal that wave pinning produces purely very directed motion in CPM, while MMOs allow for meandering and non-motile behaviors to occur. This highlights the role of MMOs as a potential mechanism for mesenchymal cell motility.