A novel integrated experimental and computational approach to unravel fibroblast motility in response to chemical gradients in 3D collagen matrices.

Abstract

Fibroblasts play an essential role in tissue repair and regeneration as they migrate to wounded areas to secrete and remodel the extracellular matrix. Fibroblasts recognize chemical substances such as growth factors, which enhance their motility towards the wounded tissues through chemotaxis. Although several studies have characterized single-cell fibroblast motility before, the migration patterns of fibroblasts in response to external factors have not been fully explored in 3D environments. We present a study that combines experimental and computational efforts to characterize the effect of chemical stimuli on the invasion of 3D collagen matrices by fibroblasts. Experimentally, we used microfluidic devices to create chemical gradients using collagen matrices of distinct densities. We evaluated how cell migration patterns were affected by the presence of growth factors and the mechanical properties of the matrix. Based on these results, we present a discrete-based computational model to simulate cell motility, which we calibrated through the quantitative comparison of experimental and computational data via Bayesian optimization. By combining these approaches, we predict that fibroblasts respond to both the presence of chemical factors and their spatial location. Furthermore, our results show that the presence of these chemical gradients could be reproduced by our computational model through increases in the magnitude of cell-generated forces and enhanced cell directionality. Although these model predictions require further experimental validation, we propose that our framework can be applied as a tool that takes advantage of experimental data to guide the calibration of models and predict which mechanisms at the cellular level may justify the experimental findings. Consequently, these new insights may also guide the design of new experiments, tailored to validate the variables of interest identified by the model.