Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 Utrecht, the Netherlands.
Université Paris Cité, CNRS, Institut Jacques Monod, 75013 Paris, France.
Cell Rep. 2022 Oct 11;41(2):111475. doi: 10.1016/j.celrep.2022.111475.
Epithelial cell divisions are coordinated with cell loss to preserve epithelial integrity. However, how epithelia adapt their rate of cell division to changes in cell number, for instance during homeostatic turnover or wounding, is not well understood. Here, we show that epithelial cells sense local cell density through mechanosensitive E-cadherin adhesions to control G2/M cell-cycle progression. As local cell density increases, tensile forces on E-cadherin adhesions are reduced, which prompts the accumulation of the G2 checkpoint kinase Wee1 and downstream inhibitory phosphorylation of Cdk1. Consequently, dense epithelia contain a pool of cells that are temporarily halted in G2 phase. These cells are readily triggered to divide following epithelial wounding due to the consequent increase in intercellular forces and resulting degradation of Wee1. Our data collectively show that epithelial cell division is controlled by a mechanical G2 checkpoint, which is regulated by cell-density-dependent intercellular forces sensed and transduced by E-cadherin adhesions.
上皮细胞的分裂与细胞丢失相协调以维持上皮组织的完整性。然而，上皮组织如何根据细胞数量的变化（例如在稳态更新或受伤期间）来调节其细胞分裂速度，目前还不太清楚。在这里，我们发现上皮细胞通过机械敏感的 E-钙黏蛋白黏附来感知局部细胞密度，从而控制 G2/M 细胞周期进程。随着局部细胞密度的增加，E-钙黏蛋白黏附的张力减小，促使 G2 检查点激酶 Wee1 的积累以及 Cdk1 的下游抑制性磷酸化。因此，密集的上皮组织中包含了一群暂时停滞在 G2 期的细胞。由于细胞间力的增加和 Wee1 的降解，这些细胞在发生上皮损伤后很容易被触发进行分裂。我们的数据表明，上皮细胞的分裂受到机械性 G2 检查点的控制，该检查点由 E-钙黏蛋白黏附感知和转导的、依赖细胞密度的细胞间力调节。
