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

JOURNAL OF THEORETICAL BIOLOGY

卷:400

Article

Nardini, John T.^1,2  Chapnick, Douglas A.³  Liu, Xuedong³  Bortz, David M.¹ 

[1] Univ Colorado, Dept Appl Math, Boulder, CO 80309 USA

[2] Univ Colorado, Interdisciplinary Quantitat Biol Grad Program, Boulder, CO 80309 USA

[3] Univ Colorado, Dept Chem & Biochem, Campus Box 215, Boulder, CO 80309 USA

关键词: Wound healing assays;    Nonlinear diffusion equations;    Collective migration;    Cell-cell adhesion;    Epidermal growth factor;    Keratinocytes;    Re-epithelialization;   

DOI  :  10.1016/j.jtbi.2016.04.015

来源: Elsevier

【 摘 要 】

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, cc-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 fails 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. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

Free