Patten Jennifer, Albeltagy Nourhan, Bonadio Jacob D, Ortez Armando, Wang Karin
bioRxiv. 2025 Apr 7:2025.04.01.646098. doi: 10.1101/2025.04.01.646098.
Cell migration is an essential step in wound healing. Mechanical input from the local microenvironment controls much of cell velocity and directionality during migration, which is translated into biochemical cues by focal adhesion kinase (FAK) inside the cell. FAK induces both regeneration and fibrosis. The mechanisms by which FAK decide wound fate (regenerative or fibrotic repair) in soft, normal wounds or stiff, fibrotic wounds remains unclear. Here we show that FAK differentially mechanoregulates wound behavior on soft substrates mimicking normal wounds and stiff substrates mimicking fibrotic wounds by converting mechanical substrate stimuli into variable cell velocity, directionality, and angle during wound healing. Cells on soft substrates migrate slower and less persistently; cells on stiff substrates migrate faster and more persistently with the same angle as the cells on normal wound substrates. Inhibition of FAK results in substantially slower, less persistent, and less correctly angled cell migration, which leads to slowed wound closure. Moreover, FAK inhibition impairs fibroblast ability to respond to substrate stiffness when migrating. Here we show FAK is an essential mechanoregulator of wound migration in fibroblast wound closure and is responsible for controlling cell migration dynamics in response to substrate stiffnesses mimicking normal or fibrotic wounds.
细胞迁移是伤口愈合的一个重要步骤。局部微环境的机械输入在细胞迁移过程中控制着大部分细胞速度和方向性，而这在细胞内通过粘着斑激酶（FAK）转化为生化信号。FAK既能诱导再生，也能导致纤维化。在柔软的正常伤口或坚硬的纤维化伤口中，FAK决定伤口转归（再生或纤维化修复）的机制仍不清楚。在此，我们表明，通过在伤口愈合过程中将机械性底物刺激转化为可变的细胞速度、方向性和角度，FAK在模拟正常伤口的柔软底物和模拟纤维化伤口的坚硬底物上对伤口行为进行差异性机械调节。在柔软底物上的细胞迁移较慢且持续性较差；在坚硬底物上的细胞迁移较快且持续性较好，其角度与正常伤口底物上的细胞相同。抑制FAK会导致细胞迁移显著变慢、持续性降低且角度偏差增大，从而导致伤口闭合减缓。此外，FAK抑制会损害成纤维细胞在迁移时对底物硬度的反应能力。在此我们表明，FAK是成纤维细胞伤口闭合过程中伤口迁移的关键机械调节因子，负责控制细胞对模拟正常或纤维化伤口的底物硬度作出反应时的迁移动态。
