Lien Jui-Chien, Wang Yu-Li
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania.
Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania.
Biophys J. 2023 Aug 8;122(15):3146-3158. doi: 10.1016/j.bpj.2023.06.019. Epub 2023 Jul 4.
Although the important role of cell intercalation within a collective has long been recognized particularly for morphogenesis, the underlying mechanism remains poorly understood. Here we investigate the possibility that cellular responses to cyclic stretching play a major role in this process. By applying synchronized imaging and cyclic stretching to epithelial cells cultured on micropatterned polyacrylamide (PAA) substrates, we discovered that uniaxial cyclic stretching induces cell intercalation along with cell shape change and cell-cell interfacial remodeling. The process involved intermediate steps as previously reported for cell intercalation during embryonic morphogenesis, including the appearance of cell vertices, anisotropic vertex resolution, and directional expansion of cell-cell interface. Using mathematical modeling, we further found that cell shape change in conjunction with dynamic cell-cell adhesions was sufficient to account for the observations. Further investigation with small-molecule inhibitors indicated that disruption of myosin II activities suppressed cyclic stretching-induced intercalation while inhibiting the appearance of oriented vertices. Inhibition of Wnt signaling did not suppress stretch-induced cell shape change but disrupted cell intercalation and vertex resolution. Our results suggest that cyclic stretching, by inducing cell shape change and reorientation in the presence of dynamic cell-cell adhesions, can induce at least some aspects of cell intercalation and that this process is dependent in distinct ways on myosin II activities and Wnt signaling.
尽管细胞在集体中插入的重要作用早已得到认可，尤其是在形态发生方面，但其潜在机制仍知之甚少。在这里，我们研究了细胞对周期性拉伸的反应在这一过程中起主要作用的可能性。通过对微图案化聚丙烯酰胺（PAA）底物上培养的上皮细胞进行同步成像和周期性拉伸，我们发现单轴周期性拉伸会诱导细胞插入，同时伴随着细胞形状变化和细胞间界面重塑。这一过程涉及到先前报道的胚胎形态发生过程中细胞插入的中间步骤，包括细胞顶点的出现、各向异性顶点分辨率以及细胞间界面的定向扩展。通过数学建模，我们进一步发现细胞形状变化与动态细胞间粘附相结合足以解释这些观察结果。用小分子抑制剂进行的进一步研究表明，肌球蛋白II活性的破坏会抑制周期性拉伸诱导的插入，同时抑制定向顶点的出现。抑制Wnt信号通路不会抑制拉伸诱导的细胞形状变化，但会破坏细胞插入和顶点分辨率。我们的结果表明，在存在动态细胞间粘附的情况下，周期性拉伸通过诱导细胞形状变化和重新定向，可以诱导细胞插入的至少某些方面，并且这一过程以不同的方式依赖于肌球蛋白II活性和Wnt信号通路。
