Investigating local negative feedback of Rac activity by mathematical models and cell motility simulations.

Area of Science:

• Cell biology
• Biophysics
• Mathematical modeling

Background:

• Directed cell migration relies on local positive feedback and long-range inhibition.
• Previous models of cell polarity lacked crucial feedback circuits, such as local negative feedback.

Purpose of the Study:

• To investigate the impact of local negative feedback on cell physiology and migration.
• To extend existing mathematical models by incorporating local negative feedback circuits.

Main Methods:

• Developed partial differential equation (PDE) models for Rac, Rac-Inhibitor, and PIP3-Rac-Inhibitor circuits.
• Used optogenetic stimulation of PI3K in neutrophil-like HL-60 cells.
• Performed 2D cell-based simulations to model cell shape, motility, and responses to stimuli.

Main Results:

• The addition of local negative feedback improved modeled cells' ability to respond to temporal and spatial guidance cues.
• Local Rac inhibition enhanced responses to noisy or dynamic extracellular gradients.
• The extended model demonstrated improved dynamic polarity and gradient sensing.

Conclusions:

• Local negative feedback is essential for enhancing dynamic polarity and gradient sensing in migratory cells.
• Mathematical modeling incorporating local negative feedback provides insights into cell migration mechanisms.
• This study highlights the importance of feedback circuits in regulating cell behavior.