title: Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures.
abstract: The growth of a well-formed epithelial structure is governed by mechanical constraints, cellular apico-basal polarity, and spatially controlled cell division. Here we compared the predictions of a mathematical model of epithelial growth with the morphological analysis of 3D epithelial structures. In both in vitro cyst models and in developing epithelial structures in vivo, epithelial growth could take place close to or far from mechanical equilibrium, and was determined by the hierarchy of time-scales of cell division, cell-cell rearrangements, and lumen dynamics. Equilibrium properties could be inferred by the analysis of cell-cell contact topologies, and the nonequilibrium phenotype was altered by inhibiting ROCK activity. The occurrence of an aberrant multilumen phenotype was linked to fast nonequilibrium growth, even when geometric control of cell division was correctly enforced. We predicted and verified experimentally that slowing down cell division partially rescued a multilumen phenotype induced by altered polarity. These results improve our understanding of the development of epithelial organs and, ultimately, of carcinogenesis.
authors.affiliation: Institute for Cancer Research and Treatment (IRCC), Candiolo 10060, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cerruti
authors.forename: Alberto
authors.initials: A
authors.lastname: Puliafito
authors.forename: Annette M
authors.initials: AM
authors.lastname: Shewan
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Combes
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
authors.forename: Federica
authors.initials: F
authors.lastname: Chianale
authors.forename: Luca
authors.initials: L
authors.lastname: Primo
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
authors.forename: Antonio
authors.initials: A
authors.lastname: Celani
authors.forename: Andrea
authors.initials: A
authors.lastname: Gamba
mesh_terms: D000818:Animals; D002450:Cell Communication; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D016764:Cell Polarity / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D003560:Cysts / Q000378:metabolism / Q000473:pathology*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009716:Numerical Analysis, Computer-Assisted; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases