School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
Science. 2022 Feb 11;375(6581):eabl8876. doi: 10.1126/science.abl8876.
Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population. We characterized leaders emerging from epithelial monolayers in cell culture and found that they activated the stress sensor p53, which was sufficient to initiate leader cell behavior. p53 activated the cell cycle inhibitor p21, which in turn induced leader behavior through inhibition of cyclin-dependent kinase activity. p53 also induced crowding hypersensitivity in leader cells such that, upon epithelial closure, they were eliminated by cell competition. Thus, mechanically induced p53 directs emergence of a transient population of leader cells that drive migration and ensures their clearance upon epithelial repair.
上皮细胞迁移穿过伤口以修复受损组织。在迁移片的前沿的先导细胞通常驱动这个过程。然而，尚不清楚先导细胞如何从明显同质的上皮细胞群体中出现。我们对细胞培养中的上皮单层中出现的先导细胞进行了表征，发现它们激活了应激传感器 p53，这足以启动先导细胞行为。p53 激活了细胞周期抑制剂 p21，p21 反过来通过抑制细胞周期蛋白依赖性激酶活性诱导先导细胞行为。p53 还诱导先导细胞对拥挤的敏感性增加，使得在上皮闭合时，它们通过细胞竞争被消除。因此，机械诱导的 p53 指导了一个短暂的先导细胞群体的出现，这些细胞驱动迁移，并确保在上皮修复时清除它们。
