Ware M F, Wells A, Lauffenburger D A
Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Cell Sci. 1998 Aug;111 ( Pt 16):2423-32. doi: 10.1242/jcs.111.16.2423.
Growth factors stimulate sustained cell migration as well as inducing select acute motility-related events such as membrane ruffling and disruption of focal adhesions. However, an in-depth understanding of the characteristics of sustained migration that are regulated by growth factor signals is lacking: how the biochemical signals are related to physical processes underlying locomotion, and how these events are coordinately influenced by interplay between growth factor and matrix substratum signals. To address these issues, we studied sustained migration of NR6 fibroblasts on a complex human matrix substratum, Amgel, comparing effects of epidermal growth factor (EGF) treatment across a range of Amgel levels. In the absence of EGF, cell migration speed and directional persistence are relatively independent of Amgel level, whereas in the presence of EGF speed is increased at intermediate Amgel levels but not at low and high Amgel levels while directional persistence is decreased at intermediate but not at low and high Amgel levels. The net effect of EGF is to increase the frequency of changes in the cell direction, and at the same time to slightly increase the path-length and thereby greatly enhance random dispersion of cells. Despite increasing migration speed during long-term sustained migration EGF treatment does not lead to significantly increased absolute rates of membrane extension in contrast to its well-known elicitation of membrane ruffling in the short term. However, EGF treatment does decrease cell spread area, yielding an apparent enhancement of specific membrane extension rate, i.e. normalized to cell spread area. Cell movement speed and directional persistence are thus, respectively, directly related and indirectly related to the increase in specific membrane extension rate (alternatively, the decrease in cell spread area) induced by EGF treatment during sustained migration. These results indicate that growth factor and matrix substrata coordinately regulate sustained cell migration through combined governance of underlying physical processes.
生长因子刺激细胞持续迁移，并诱导一些特定的急性运动相关事件，如膜皱襞形成和粘着斑的破坏。然而，目前缺乏对生长因子信号调控的持续迁移特征的深入理解：生化信号如何与运动的物理过程相关，以及这些事件如何受到生长因子和基质信号之间相互作用的协同影响。为了解决这些问题，我们研究了NR6成纤维细胞在复杂的人基质底物Amgel上的持续迁移，比较了在一系列Amgel水平下表皮生长因子（EGF）处理的效果。在没有EGF的情况下，细胞迁移速度和方向持续性相对独立于Amgel水平，而在有EGF存在时，中间Amgel水平下速度增加，但低和高Amgel水平下则不然，而方向持续性在中间水平降低，但低和高Amgel水平下则不然。EGF的净效应是增加细胞方向变化的频率，同时略微增加路径长度，从而极大地增强细胞的随机扩散。尽管在长期持续迁移过程中EGF处理增加了迁移速度，但与它在短期内引发膜皱襞形成的情况相反，EGF处理并未导致膜延伸的绝对速率显著增加。然而，EGF处理确实会减小细胞铺展面积，从而使特定膜延伸速率（即相对于细胞铺展面积进行归一化）明显增强。因此，在持续迁移过程中，细胞运动速度和方向持续性分别与EGF处理诱导的特定膜延伸速率增加（或者说细胞铺展面积减小）直接相关和间接相关。这些结果表明，生长因子和基质底物通过对潜在物理过程的联合调控来协同调节细胞的持续迁移。
