A mathematical model of intercellular signaling during epithelial wound healing

TL;DR

This paper presents a mathematical model explaining the two-wave MAPK activity observed during epithelial wound healing, emphasizing ROS and ligand interactions and cell movement-induced stresses.

Contribution

It introduces a minimal diffusion-convection model capturing the biphasic MAPK response and explores its mathematical properties related to bistability and wave solutions.

Findings

Model reproduces observed MAPK wave patterns

Highlights role of ROS and ligand competition in signaling

Connects cell movement stresses to sustained MAPK activity

Abstract

Recent experiments in epithelial wound healing have demonstrated the necessity of Mitogen-activated protein kinase (MAPK) for coordinated cell movement after damage. This MAPK activity is characterized by two wave-like phenomena. One MAPK "wave" that originates immediately after injury, propagates deep into the cell layer, and then rebounds back to the wound interface. After this initial MAPK activity has largely disappeared, a second MAPK front propagates slowly from the wound interface and continues into the tissue, maintaining a sustained level of MAPK activity throughout the cell layer. It has been suggested that the first wave is initiated by reactive oxygen species (ROS) generated at the time of injury. In this paper, we develop a minimal mechanistic diffusion-convection model that reproduces the observed behavior. The main ingredients of our model are a competition between ligand (e.g., Epithelial Growth Factor) and ROS for the activation of Epithelial Growth Factor Receptor (EGFR) and a second MAPK wave that is sustained by stresses induced by the slow cell movement that closes the wound. We explore the mathematical properties of the model in connection with the bistability of the MAPK cascade and look for traveling wave solutions consistent with the experimentally observed MAPK activity patterns.