Computational modeling of epithelial wound healing: Short and long term chemo-mechanical mechanisms

Abstract

During the lifetime of all living multicellular organisms, wounds in their tissues are frequently observed. The capability of closing those gaps is fundamental for a healthy development. If done deficiently, many diseases may occur from simple inflammation to tumor formation. The wound healing process in epithelial tissue occurs in three different stages. The first one is the assembly of a supra-cellular actomyosin cable and its migration towards the wound edge, triggered by biochemical processes in which calcium plays a distinctive role. How this process is orchestrated following damage remains unclear. Later, after its positioning, the cable contracts driving the tissue towards the gap and reducing the wound area. Finally, cell migration towards the interior of the wound ends up sealing the tissue. In this work, we make use of a mechanical continuum model for the first two stages in order to developed and 2D finite element simulations within a monolithically fully implicit implementation. The model for the actomyosin cable formation involves the coupling of transient calcium ions transport, with actin fibers and myosin motors recruitment and non-linear mechanical response of the tissue. The contraction stage, the active deformation of the previously formed actomyosin cable is taken into account. The relative motion of the myosin motors over the actin filaments is modeled so there exists an active tissue contraction in the direction of those fibers. Upon implementation, the model is capable of performing a wide range of biophysical situations reported experimentally, as we demonstrate in our numerical results. We have been able to rationalize through computational mechanics the firing of calcium in the wound right after damage infliction as well as the consequent formation of actin ring, reproducing nicely what has been reported in biological literature. Thereafter, the numerical model of acto-myosin contraction, fully integrated with the non-linear mechanics of the problem, correlates with the mechanics of wound closure at the actin-ring contraction stage. More importantly, the approach is the first of its kind in the modeling of epithelial and embryonic cell layers, where a wide number of complex mechanics has been integrated and solved though computational methods in engineering. We believe that the simulations will help to unravel new insights in open questions of developmental biology.