Modeling keratinocyte wound healing dynamics: Cell–cell adhesion promotes sustained collective migration

Abstract

The in vitro migration of keratinocyte cell sheets displays behavioral and biochemical similarities to the in vivo wound healing response of keratinocytes in animal model systems. In both cases, ligand-dependent Epidermal Growth Factor Receptor (EGFR) activation is sufficient to elicit collective cell migration into the wound. Previous mathematical modeling studies of in vitro wound healing assays assume that physical connections between cells have a hindering effect on cell migration, but biological literature suggests a more complicated story. By combining mathematical modeling and experimental observations of collectively migrating sheets of keratinocytes, we investigate the role of cell-cell adhesion during in vitro keratinocyte wound healing assays. We develop and compare two nonlinear diffusion models of the wound healing process in which cell-cell adhesion either hinders or promotes migration. Both models can accurately fit the leading edge propagation of cell sheets during wound healing when using a time-dependent rate of cell-cell adhesion strength. The model that assumes a positive role of cell-cell adhesion on migration, however, is robust to changes in the leading edge definition and yields a qualitatively accurate density profile. Using RNAi for the critical adherens junction protein, α-catenin, we demonstrate that cell sheets with wild type cell-cell adhesion expression maintain migration into the wound longer than cell sheets with decreased cell-cell adhesion expression, which fail to exhibit collective migration. Our modeling and experimental data thus suggest that cell-cell adhesion promotes sustained migration as cells pull neighboring cells into the wound during wound healing.

The Designer Antimicrobial Peptide A-hBD-2 Facilitates Skin Wound Healing by Stimulating Keratinocyte Migration and Proliferation

“…Its activation stimulates cell migration and proliferation in wounds and thus promotes healing [21]. When EGFR protein expression is suppressed, the level of p-STAT3 protein also decreases [22].…”

Fibroblasts promote the collective invasion of ameloblastoma tumor cells in a 3D coculture model

“…Moreover, pathological images of all types of this tumor demonstrate that ameloblastoma cells invade collectively into surrounding tissues without disrupting their cell-cell contacts [4,11,12]. Collective cellular invasion is considered to be important during morphogenesis and in pathological processes such as wound healing and cancer cell invasion [13][14][15], but the details of this invasive mechanism are unknown. To the best of our knowledge, no reports have examined cellular factors that may affect the different styles of invasive growth in ameloblastoma.…”

Local meshless method for PDEs arising from models of wound healing

“…Numerical solutions of such types of wound healing models have been considered recently by a few researchers (see [1,11,12,20,28,44,49,50,53] and the references therein). These include finitevolume method coupled with flux limiting [11,12,44], finite-element method [20], cut-cell finiteelement method [53], standard Galerkin finite-element method with piecewise linear functions [49], Galerkin finite-element method with linear triangular elements [48], method of line approach [1,28] and finite-difference method [50].…”

“…These include finitevolume method coupled with flux limiting [11,12,44], finite-element method [20], cut-cell finiteelement method [53], standard Galerkin finite-element method with piecewise linear functions [49], Galerkin finite-element method with linear triangular elements [48], method of line approach [1,28] and finite-difference method [50]. All these methods are mesh-based methods and their collective limitation is that they are hard to be implemented on irregular geometries.…”