Cellular and molecular responses of epithelial cells to distinct forms of cell death.

摘要

Epithelial cells continuously turnover and therefore require dynamic changes in their neighboring cells to prevent a breach in this protective barrier. Although it is clear that dying cells can have a profound effect on epithelial tissue homeostasis, the mechanisms by which epithelial cells respond to death of a neighboring cell remain poorly understood. Progress in studies on the impact of dying cells on their neighboring epithelial cells is impeded by the dearth of experimental methods for inducing cell death in individual cells without globally exposing the epithelial monolayer to death-activating stimuli. Apoptosis is the most common mechanism by which unwanted cells are eliminated in epithelial tissues. Likewise, necrosis plays an important role in various pathological conditions, including tumorigenesis. Using microinjection, we established an experimental model to induce apoptosis and necrosis with high spatial and temporal specificity. Using live cell imaging and quantitative image analysis, we have analyzed the effects of apoptosis and necrosis on the neighboring epithelial cells. We demonstrate that removal of an apoptotic cell is mediated by mechanical stimulation exerted by the dying cell that triggers coordinated elongation of the neighboring cells. The mechanical signal is transduced through E-cadherin-mediated cell-cell adhesion that also controls the coordinated response of the neighboring cells. Accordingly, elongation and extrusion are compromised in cells that express low levels of E-cadherin and these cells display loss of barrier function in response to apoptotic stimuli. In contrast, when necrosis is induced in an epithelial cell, elongation of the neighboring cells is not observed. Instead, necrotic cell death is associated with temporary loss of cell-cell adhesion and triggers lamellipodial extension of the neighboring cells. Additionally, we found that necrotic cells stimulate proliferation of the surrounding epithelial cells through an unidentified secreted factor. These findings indicate that activation of necrotic cell death is likely to affect epithelial homeostasis and contribute to disease susceptibility by directly modulating the behavior of the neighboring epithelial cells. Together, these findings indicate that proper control of adhesive forces throughout epithelial cell turnover is a common theme in apoptotic and necrotic cell death that might serve as a protective mechanism against disease states.