title: Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia.
abstract: 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.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, Utah 84112, USA.
authors.forename: George T
authors.initials: GT
authors.lastname: Eisenhoffer
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Loftus
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yoshigi
authors.forename: Hideo
authors.initials: H
authors.lastname: Otsuna
authors.forename: Chi-Bin
authors.initials: CB
authors.lastname: Chien
authors.forename: Paul A
authors.initials: PA
authors.lastname: Morcos
authors.forename: Jody
authors.initials: J
authors.lastname: Rosenblatt
mesh_terms: D058500:Animal Fins / Q000033:anatomy & histology / Q000166:cytology / Q000196:embryology; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D016923:Cell Death; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003106:Colon / Q000166:cytology; D004285:Dogs; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D004847:Epithelial Cells / Q000166:cytology*; D006706:Homeostasis; D006801:Humans; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D007473:Ion Channels; D008246:Lysophospholipids; C572766:Piezo1 protein, zebrafish; D029961:Zebrafish Proteins; C060506:sphingosine 1-phosphate; D013110:Sphingosine