Andasari Vivi, Lü Dongyuan, Swat Maciej, Feng Shiliang, Spill Fabian, Chen Li, Luo Xiangdong, Zaman Muhammad, Long Mian
Boston University, Department of Biomedical Engineering, 44 Cummington Mall, Boston, MA 02215, USA.
Integr Biol (Camb). 2018 Oct 15;10(10):605-634. doi: 10.1039/c8ib00048d.
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.
人们普遍认为，角质形成细胞迁移在伤口再上皮化过程中起着关键作用。该功能的缺陷会导致伤口复发，引发严重的临床问题。多项体外研究表明，迁移的角质形成细胞的速度可由表皮生长因子（EGF）调节，EGF会影响角质形成细胞的整合素表达。由于实验表明，由于整合素表达增加导致的黏附增加会因细胞速度对黏附的双相依赖性而减缓细胞迁移，所以EGF刺激产生的整合素表达（通过细胞-基质黏附）与角质形成细胞迁移速度之间的关系并非线性。在我们之前的研究中，我们发现与EGF增强的成纤维细胞共培养的角质形成细胞形成了一种不对称迁移模式，即朝着成纤维细胞迁移的角质形成细胞的累积距离小于远离成纤维细胞迁移的角质形成细胞的累积距离。这种不对称模式被认为是由成纤维细胞分泌的高浓度EGF引发的。EGF通过旁分泌信号刺激朝着成纤维细胞迁移的角质形成细胞表面整合素受体的表达。在本文中，我们使用细胞Potts模型（CPM）提出了一种由成纤维细胞分泌的EGF控制的角质形成细胞迁移计算模型。我们的计算模拟结果证实了实验中观察到的不对称模式。这些结果为我们深入理解生长因子梯度存在下角质形成细胞迁移的复杂性提供了帮助，并可能解释受损伤口愈合过程中的再上皮化失败。
