Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia
By G. T. Eisenhoffer, Patrick D. Loftus, M. Yoshigi, H. Otsuna, C. Chien, P. Morcos, J. Rosenblatt. Nature, 2012
830 citations recorded by the source corpus.
For an epithelium to provide a protective barrier, it must maintain homeostatic cell numbers by matching the number of dividing cells with the number of dying cells. Although compensatory cell division can be triggered by dying cells, it is unknown how cell death might relieve overcrowding due to proliferation. When we trigger apoptosis in epithelia, dying cells are extruded to preserve a functional barrier. Extrusion occurs by cells destined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes the dying cell out. However, it is not clear what drives cell death during normal homeostasis. Here we show in human, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusion of live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highest crowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro. Like apoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine 1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signalling through stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, in zebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal that during homeostatic turnover, growth and division of epithelial cells on a confined substratum cause overcrowding that leads to their extrusion and consequent death owing to the loss of survival factors. These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents the accumulation of excess epithelial cells.
Subfields: Cell Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/9261f5df906647becb5bbe359fa302f862aefefd
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Citations in the corpus
- Intestinal permeability – a new target for disease prevention and therapy (2014, background): “Recent studies have shown that under physiological healthy conditions epithelial extrusion is triggered by stretching of the epithelial cell, which is detected by activation of the stretch-sensitive cation channel Piezo [31].”
- Forces in tissue morphogenesis and patterning. (2013, positive): “In Drosophila and zebrafish, compression force associated with overcrowding is proposed to lead to extrusion of live cells from epithelia (Eisenhoffer et al., 2012; Marinari et al., 2012).”
- Chaste: An Open Source C++ Library for Computational Physiology and Biology (2013, background): “A hypothesis generated following Chaste simulations related to cellular extrusion in the crypt [42] was verified experimentally in independent investigations, published at a similar time [43].”
- Reverse genetic screening reveals poor correlation between Morpholino-induced and mutant phenotypes in zebrafish (2014, background): “…sa tll1 dorsalized, loss of tail fin ND (Lele et al., 2001) dorsalized, loss of tail fina sa fam38a gastrulation defective, fin blistering ND (Eisenhoffer et al., 2012) normal um linc:birc6 hindbrain ventricle inflation yes (Ulitsky et al., 2011) normal um appl1 necrosis, short yolk…”