Department of Physics, Institute for Biophysical Dynamics, James Franck Institute, University of Chicago, Chicago, IL 60637.
Department of Physics, BioInspired Institute, Syracuse University, Syracuse, NY 13244.
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). doi: 10.1073/pnas.1917853118.
Epithelia have distinct cellular architectures which are established in development, reestablished after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here, we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here, we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop an extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly, but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics are arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions, the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics.
上皮细胞具有独特的细胞结构，这些结构在发育过程中建立，在创伤后重新建立，并在组织稳态中维持，尽管存在细胞更替和机械扰动。反过来，细胞形状也通过调节细胞分化、增殖和迁移来控制组织功能。在这里，我们研究了模型上皮单层中的细胞形状变化。在达到汇合后，细胞会继续增殖并随时间改变形状，最终导致以运动停止和更规则的细胞形状为特征的最终结构。这种单层重塑是稳健的，具有相似的定性演化在细胞形状和动力学观察到不同的扰动。在这里，我们通过活性顶点模型量化单层重塑的差异，以确定控制上皮结构的潜在序参量。当单层形成在具有不同刚度的细胞外基质上时，我们发现运动停止时的细胞密度变化显著，但细胞形状保持不变，这与组织刚性的出现一致。相比之下，药理学扰动可以显著改变组织动力学停止时的细胞形状，这与组织内的活性应力量不同一致。在所有实验条件下，最终的细胞形状与细胞增殖率密切相关，细胞周期抑制会立即停止细胞运动。最后，我们证明了细胞连接张力的细胞周期变化是单层内活性应力的一个来源。因此，上皮组织的结构和力学可以来源于细胞力学和细胞周期动力学产生的应力之间的相互作用。
