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Abstract

To find sites of infection, neutrophil cells, the immune system’s first responders, must polarize, establishing a clear front and back, to enable directed migration. This polarization is regulated by the GTPase protein Rac. One minimal model by Mori et al. (2018) captures this polarizing behaviour using a reaction–diffusion (RD) system, namely the ``Wave-Pinning" (WP) model. A recent publication by Town and Weiner (2023) tracked Rac activity in neutrophil-like migratory cells, recording both temporal and spatial profiles of Rac as well as the resulting cell trajectories under different stimulation protocols. In collaboration with Orion Weiner’s lab (UCSF), I evaluated variants of the WP model against experimental datasets. Town and Weiner hypothesized the existence of a local Rac inhibitor downstream of active Rac. I extend the WP framework by introducing this feedback loop and test whether it can explain the observed data. To simulate migratory cells while solving the RD system inside the cell, I used the Cellular Potts Model (CPM), with partial differential equations solved along the 1D cell edge. To simulate cell shape and migration, I used the CPM (implemented in open-source software, Morpheus) to capture cell morphodynamics, with the RD system solved along the cell edge; high Rac was assumed to promote edge protrusion. I show that the hypothesized local Rac inhibitor enables the model to reproduce both qualitative and quantitative experimental results, including key cell trajectories. The inhibitor also enhances the cell’s ability to track stimuli. However, to account for other observed behaviours, I showed that an upstream intermediate (PIP3) plays an important role. Together, the WP-Inhibitor-PIP3 model suffices to explain the dataset, providing a minimal mechanistic model of Rac regulation consistent with experimental observations.