It is widely agreed that keratinocyte migration plays a crucial role in wound re-epithelialization. Defects in this function contribute to wound reoccurrence causing significant clinical problems. Several in vitro studies have shown that the speed of migrating keratinocytes can be regulated by epidermal growth factor (EGF) which affects keratinocyte's integrin expression. The relationship between integrin expression (through cell–matrix adhesion) stimulated by EGF and keratinocyte migration speed is not linear since increased adhesion, due to increased integrin expression, has been experimentally shown to slow down cell migration due to the biphasic dependence of cell speed on adhesion. In our previous work we showed that keratinocytes that were co-cultured with EGF-enhanced fibroblasts formed an asymmetric migration pattern, where, the cumulative distances of keratinocytes migrating toward fibroblasts were smaller than those migrating away from fibroblasts. This asymmetric pattern is thought to be provoked by high EGF concentration secreted by fibroblasts. The EGF stimulates the expression of integrin receptors on the surface of keratinocytes migrating toward fibroblasts via paracrine signaling. In this paper, we present a computational model of keratinocyte migration that is controlled by EGF secreted by fibroblasts using the Cellular Potts Model (CPM). Our computational simulation results confirm the asymmetric pattern observed in experiments. These results provide a deeper insight into our understanding of the complexity of keratinocyte migration in the presence of growth factor gradients and may explain re-epithelialization failure in impaired wound healing.

中文翻译：

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伤口愈合的计算模型：成纤维细胞分泌的EGF促进上皮角质形成细胞的延迟上皮再形成

人们普遍认为，角质形成细胞迁移在伤口上皮再生中起着至关重要的作用。此功能的缺陷会导致伤口复发，从而引起严重的临床问题。几种体外研究表明，迁移角质形成细胞的速度可以通过影响角质形成细胞整联蛋白表达的表皮生长因子（EGF）来调节。EGF刺激的整联蛋白表达（通过细胞-基质粘附）与角质形成细胞迁移速度之间的关系不是线性的，因为实验表明，由于整联蛋白表达增加，粘附增加会减慢细胞迁移，这是由于细胞速度对附着力。在我们以前的工作中，我们发现与增强了EGF的成纤维细胞共培养的角质形成细胞形成了不对称迁移模式，其中，向成纤维细胞迁移的角质形成细胞的累积距离小于从成纤维细胞迁移的角质形成细胞的累积距离。据认为，这种不对称模式是由成纤维细胞分泌的高EGF浓度引起的。EGF刺激向成纤维细胞迁移的角质形成细胞表面上整联蛋白受体的表达通过旁分泌信号传导。在本文中，我们介绍了一个角质形成细胞迁移的计算模型，该模型受成纤维细胞分泌的EGF使用Cellular Potts模型（CPM）的控制。我们的计算仿真结果证实了实验中观察到的不对称模式。这些结果为我们对在存在生长因子梯度的情况下角质形成细胞迁移的复杂性的理解提供了更深刻的见解，并可能解释了伤口愈合不良中的再上皮化失败。