Spatio-temporal multiscale cell modeling of skin wound healing.

Abstract

Human skin wound healing is a complex process of tissue pattern formation driven by massive cell migration and regeneration, coordinated through intercellular communication. A multiscale tissue modeling framework, the dynamic cellular finite-element method (DyCelFEM), was developed to more realistically study the wound healing process in silico with detailed cellular mechanical interactions and geometric changes. Cells produce and release signaling cytokines that diffuse through the extracellular matrix (ECM) to mediate cell communication. Cell behavior control was integrated into each individual cell, based on cell type and intracellular circuits, to enable individual stochastic decisions regarding growth, proliferation, migration, and death. This allowed cells to respond to environmental changes and signaling from surrounding cells. Model parameters were set based on available biologic data, and 10 independent simulations were conducted for each skin wound healing scenario to obtain the average dynamics and statistics. Simulation results were compared with data from experimental wounds. Results showed that the model was able to correctly reproduce the qualitative emergent behavior observed in histological imaging of wound healing. Additionally, simulations correctly captured the longitudinal dynamics of transforming growth factor β and collagen expression from gene array analysis. The successful capture of experimental observations and data served as a qualification for the model. By comparing simulated wound healing phenotypes under transforming growth factor β levels above and below physiologic normal ones, the model revealed that the ECM is likely to play a key role in transmitting critical cytokine signals to coordinate cell migration and regeneration during wound healing. Dysregulated ECM production, which produces either too much or too little ECM during wound healing, might compromise the outcome. This mechanism suggests that optimal wound healing requires a finely controlled ECM regeneration, and that therapeutics that induce significant increases in ECM might not be beneficial.