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Summary The control of tissue growth, which is a key to maintain the protective barrier function of the epithelium, depends on the balance between cell division and cell extrusion rates [ 1, 2 ]. Cells within confluent epithelial layers undergo cell extrusion, which relies on cell-cell interactions [ 3 ] and actomyosin contractility [ 4, 5 ]. Although it has been reported that cell extrusion is also dependent on cell density [ 6, 7 ], the contribution of tissue mechanics, which is tightly regulated by cell density [ 8–12 ], to cell extrusion is still poorly understood. By measuring the multicellular dynamics and traction forces, we show that changes in epithelial packing density lead to the emergence of distinct modes of cell extrusion. In confluent epithelia with low cell density, cell extrusion is mainly driven by the lamellipodia-based crawling mechanism in the neighbor non-dying cells in connection with large-scale collective movements. As cell density increases, cell motion is shown to slow down, and the role of a supracellular actomyosin cable formation and its contraction in the neighboring cells becomes the preponderant mechanism to locally promote cell extrusion. We propose that these two distinct mechanisms complement each other to ensure proper cell extrusion depending on the cellular environment. Our study provides a quantitative and robust framework to explain how cell density can influence tissue mechanics and in turn regulate cell extrusion mechanisms. [ABSTRACT FROM AUTHOR]

For the maintenance of epithelial homeostasis, various aberrant or dysfunctional cells are actively eliminated from epithelial layers. This cell extrusion process mainly falls into two modes: cell-competition-mediated extrusion and apoptotic extrusion. However, it is not clearly understood whether and how these processes are governed by common molecular mechanisms. In this study, we demonstrate that the reactive oxygen species (ROS) levels are elevated within a wide range of epithelial layers around extruding transformed or apoptotic cells. The downregulation of ROS suppresses the extrusion process. Furthermore, ATP is extracellularly secreted from extruding cells, which promotes the ROS level and cell extrusion. Moreover, the extracellular ATP and ROS pathways positively regulate the polarized movements of surrounding cells toward extruding cells in both cell-competition-mediated and apoptotic extrusion. Hence, extracellular ATP acts as an "extrude me" signal and plays a prevalent role in cell extrusion, thereby sustaining epithelial homeostasis and preventing pathological conditions or disorders. [Display omitted] • ROS level is elevated in epithelia around extruding transformed or apoptotic cells • ATP is extracellularly secreted from extruding cells, which promotes the ROS level • Extracellular ATP and ROS regulate the polarized movement of the surrounding cells • Extracellular ATP and ROS promote the extrusion of transformed or apoptotic cells Mori et al. show that during either cell-competition-mediated extrusion or apoptotic extrusion, ATP is secreted from extruding cells, which promotes the ROS level and regulates the polarized movements of surrounding cells toward extruding cells. Thus, extracellular ATP acts as an "extrude me"' signal and plays a prevalent role in cell extrusion. [ABSTRACT FROM AUTHOR]

Extrusion is a mechanism used to eliminate unfit, excess, or dying cells from epithelial tissues. The initial events guiding which cells will be selectively extruded from the epithelium are not well understood. Here, we induced damage in a subset of epithelial cells in the developing zebrafish and used time-lapse imaging to examine cell and cytoskeletal dynamics leading to extrusion. We show that cell extrusion is preceded by actomyosin contractions that are pulsatile. Our data show that pulsatile contractions are induced by a junctional to medial re-localization of myosin. Analysis of cell area during contractions revealed that cells pulsing with the longest duration and highest amplitude undergo progressive area loss and extrude. Although pulses were driven by local increases in tension, damage to many cells promoted an overall decrease in the tensile state of the epithelium. We demonstrate that caspase activation leads to sphingosine-1-phosphate enrichment that controls both tissue tension and pulses to dictate areas of extrusion. These data suggest that the kinetics of pulsatile contractions define a key behavioral difference between extruding and non-extruding cells and are predictive of extrusion. Altogether, our study provides mechanistic insight into how localized changes in physical forces are coordinated to remove defective cells for homeostatic maintenance of living epithelial tissues. [Display omitted] • Cell extrusion is preceded by actomyosin pulsatile contractions • Kinetics of pulsatile contractions are predictive of cell extrusion • Pulsatile contractions are generated by an apicomedial myosin network • Caspase activation and S1P enrichment induce pulsatile contractions Atieh et al. investigate the mechanics underlying epithelial cell extrusion. They show that dynamic pulsatile contractions emerge following cellular damage and promote extrusion of apoptotic cells. Caspase activation leads to sphingosine-1-phosphate enrichment that controls both tissue tension and pulses to dictate areas of extrusion. [ABSTRACT FROM AUTHOR]

During apoptosis, or programmed cell death, a dead cell could be expelled from the tissue by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven by actomyosin cable formation and its contraction and lamellipodial crawling of the neighboring cells [ 1–4 ]. Throughout cell extrusion, the mechanical coupling of epithelia needs to be maintained in order to preserve tissue homeostasis [ 1 ]. Although much is known about the regulation of adherens junctions (AJs) in apoptotic cell extrusion [ 4–7 ], the role and dynamics of desmosomal junctions (DJs) during this process remain poorly understood. Here, we show that DJs stay intact throughout and are crucial for cell extrusion. Pre-existing DJs between the apoptotic cell and neighboring cells remain intact, even during the formation of de novo DJs between non-dying cells, suggesting the neighboring cells possess two DJs in the middle of apoptotic cell extrusion. We further found that an actomyosin cable formed in the vicinity of DJs upon apoptosis and subsequently deviated from DJs during its constriction. Interestingly, the departure of the actomyosin cable from DJs coincided with the timing when DJs lost their straightness, suggesting a release of junctional tension at DJs and a mechanical coupling between DJs and actomyosin contractility. The depletion of desmoplakin resulted in defective contractility and an inability to form de novo DJs, leading to a failure of apoptotic cell extrusion. Our study provides a framework to explain how desmosomes play pivotal roles in maintaining epithelial sheet integrity during apoptotic cell extrusion. • Desmosomal junctions (DJs) remains intact during apoptotic cell extrusion • Neighboring non-dying cells possess two DJs in the middle of cell extrusion • Depletion of desmoplakin leads to a failure of cell extrusion • DJs govern actomyosin contractility in static epithelium and apoptotic cell extrusion Thomas et al. show pivotal role of desmosomal junction in governing actomyosin contractility and maintenance of epithelial sheet integrity during apoptotic cell extrusion. We speculate that desmoplakin-depleted tissues could lead to pathological conditions through defective actomyosin contractility and/or apoptotic cell clearance. [ABSTRACT FROM AUTHOR]

When oncogenic transformation or apoptosis occurs within epithelia, the harmful or dead cells are apically extruded from tissues to maintain epithelial homeostasis. However, the underlying molecular mechanism still remains elusive. In this study, we first show, using mammalian cultured epithelial cells and zebrafish embryos, that prior to apical extrusion of RasV12-transformed cells, calcium wave occurs from the transformed cell and propagates across the surrounding cells. The calcium wave then triggers and facilitates the process of extrusion. IP 3 receptor, gap junction, and mechanosensitive calcium channel TRPC1 are involved in calcium wave. Calcium wave induces the polarized movement of the surrounding cells toward the extruding transformed cells. Furthermore, calcium wave facilitates apical extrusion, at least partly, by inducing actin rearrangement in the surrounding cells. Moreover, comparable calcium propagation also promotes apical extrusion of apoptotic cells. Thus, calcium wave is an evolutionarily conserved, general regulatory mechanism of cell extrusion. • Calcium wave propagates from extruding cells within the epithelium • Calcium wave promotes apical extrusion of transformed or apoptotic cells • IP 3 R, gap junction, and TRPC1 are involved in calcium wave • Calcium wave induces polarized movement of surrounding cells toward extruding cells Takeuchi et al. demonstrate, using mammalian cell culture and zebrafish embryos, that calcium wave explosively propagates from extruding cells toward the surrounding cells within epithelia. Calcium wave promotes apical extrusion of transformed or apoptotic cells by inducing the polarized movement of the surrounding cells toward extruding cells. [ABSTRACT FROM AUTHOR]