Adhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion

ABSTRACT Apoptotic extrusion is crucial in maintaining epithelial homeostasis and has implications in diseases of epithelial tissues. Current literature supports that epithelia respond to extrusion to maintain their integrity by the formation of a supracellular actomyosin ring (purse-string) in the neighbors that encompasses the dying cells. However, little is known about whether other types of actin structures could contribute to extrusion as well as how forces generated by mechanosensitive proteins in the cells are integrated. Here, we found that during extrusion, a heterogeneous actin network composed of lamellipodia protrusions and discontinuous actomyosin cables, was reorganized in the neighboring cells and was the main factor driving extrusion forwards. The early presence of basal lamellipodia protrusion participated both in basal sealing of the extrusion site and in orienting the actomyosin purse-string at the later stage of extrusion. These sequential events are essential in ensuring a successful extrusion in apicobasal direction. The co-existence of these two mechanisms is determined by the interplay between the cell-cell and cell-substrate adhesions. A theoretical model integrates the role of these cellular mechanosensitive components to explain why a dual-mode mechanism, which combined lamellipodia protrusion and purse-string contractility, leads to more efficient extrusion than a single-mode mechanism. We anticipate that our approach will be useful to provide mechanistic insight into epithelial homeostasis, morphogenetic events and tumorigenesis.