Collagen gel overlay induces apoptosis of polarized cells in cultures: Disoriented cell death

We attempted to investigate the response of cells, such as cell lines of epithelial (MDCK, LLC-PK₁), endothelial (BAEC) and mesenchymal (ESK-4 and NIH3T3) origins, to inappropriate interaction with the extracellular matrix. Under conditions of collagen gel overlay, MDCK cells underwent membrane remodeling and gradually developed lumen formation within 24 h. In addition, apoptosis could be observed following the cell remodeling. The ratio of apoptosis was enhanced from 12.1 ± 2.4% within 24 h to 58.4±.8% at day 3 and finally the monolayer disintegrated. The collagen gel overlay-induced apoptosis was not a result of physical stress, since agarose gel overlay did not induce any morphological alteration. All epithelial and endothelial cells examined developed apoptosis in response to collagen overlay. In contrast, collagen overlay did not affect the growth of fibroblasts. The collagen overlay-induced apoptosis seems to be a unique phenomenon for polarized cells. Lowering the cell density delayed the onset of disoriented cell death. Cycloheximide and overexpression of Bcl-2 conferred survival for MDCK cells in response to collagen overlay. Furthermore, anti-α2 integrin antibody could abolish collagen overlay-induced morphological changes and apoptosis in MDCK cells, indicating that signals through α2 integrin on the apical membrane should be responsible for the disoriented cell death. These findings indicate that inappropriate cell-matrix interaction results in apoptosis of polarized cells, which may be responsible for cell death during developmental process or under pathological conditions.