Department of Mechanical Engineering and Materials Science, Washington University, Saint Louis, MO 63130, USA.
Department of Biomedical Engineering, Washington University, Saint Louis, MO 63130, USA.
Biomaterials. 2017 Nov;146:146-155. doi: 10.1016/j.biomaterials.2017.09.012. Epub 2017 Sep 8.
During morphogenesis and cancer metastasis, grouped cells migrate through tissues of dissimilar stiffness. Although the influence of matrix stiffness on cellular mechanosensitivity and motility are well-recognized, it remains unknown whether these matrix-dependent cellular features persist after cells move to a new microenvironment. Here, we interrogate whether priming of epithelial cells by a given matrix stiffness influences their future collective migration on a different matrix - a property we refer to as the 'mechanical memory' of migratory cells. To prime cells on a defined matrix and track their collective migration onto an adjoining secondary matrix of dissimilar stiffness, we develop a modular polyacrylamide substrate through step-by-step polymerization of different PA compositions. We report that epithelial cells primed on a stiff matrix migrate faster, display higher actomyosin expression, form larger focal adhesions, and retain nuclear YAP even after arriving onto a soft secondary matrix, as compared to their control behavior on a homogeneously soft matrix. Priming on a soft ECM causes a reverse effect. The depletion of YAP dramatically reduces this memory-dependent migration. Our results present a previously unidentified regulation of mechanosensitive collective cell migration by past matrix stiffness, in which mechanical memory depends on YAP activity.
在形态发生和癌症转移过程中，成群的细胞会穿过不同硬度的组织迁移。尽管基质硬度对细胞的机械敏感性和迁移性的影响已经得到很好的认识，但仍不清楚这些依赖于基质的细胞特征是否会在细胞迁移到新的微环境后持续存在。在这里，我们研究了特定基质硬度对上皮细胞的初始作用是否会影响它们在不同基质上的未来集体迁移——我们将这种特性称为迁移细胞的“力学记忆”。为了在上定义的基质上对细胞进行预编程，并跟踪它们在具有不同硬度的相邻次级基质上的集体迁移，我们通过逐步聚合不同的 PA 成分开发了一种模块化的聚丙烯酰胺基质。我们报告说，与在均质软基质上的对照行为相比，在上硬基质上预编程的上皮细胞迁移速度更快，肌动球蛋白表达更高，形成更大的焦点粘连，并且核 YAP 甚至在到达软次级基质后仍然存在。在软 ECM 上的预编程会产生相反的效果。YAP 的耗竭显著降低了这种依赖于力学记忆的迁移。我们的结果提出了一种以前未被识别的机制，即过去的基质硬度对机械敏感的细胞集体迁移进行调节，其中力学记忆取决于 YAP 活性。
