Dataset Information

Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia.

ABSTRACT: Mechanisms that sense and regulate epithelial morphogenesis, integrity, and homeostasis are incompletely understood. Protease-activated receptor 2 (Par2), the Par2-activating membrane-tethered protease matriptase, and its inhibitor, hepatocyte activator inhibitor 1 (Hai1), are coexpressed in most epithelia and may make up a local signaling system that regulates epithelial behavior. We explored the role of Par2b in matriptase-dependent skin abnormalities in Hai1a-deficient zebrafish embryos. We show an unexpected role for Par2b in regulation of epithelial apical cell extrusion, roles in regulating proliferation that were opposite in distinct but adjacent epithelial monolayers, and roles in regulating cell-cell junctions, mobility, survival, and expression of genes involved in tissue remodeling and inflammation. The epidermal growth factor receptor Erbb2 and matrix metalloproteinases, the latter induced by Par2b, may contribute to some matriptase- and Par2b-dependent phenotypes and be permissive for others. Our results suggest that local protease-activated receptor signaling can coordinate cell behaviors known to contribute to epithelial morphogenesis and homeostasis.

SUBMITTER: Schepis A

PROVIDER: S-EPMC5839797 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia.

Schepis Antonino A Barker Adrian A Srinivasan Yoga Y Balouch Eaman E Zheng Yaowu Y Lam Ian I Clay Hilary H Hsiao Chung-Der CD Coughlin Shaun R SR

The Journal of cell biology 20180104 3

Mechanisms that sense and regulate epithelial morphogenesis, integrity, and homeostasis are incompletely understood. Protease-activated receptor 2 (Par2), the Par2-activating membrane-tethered protease matriptase, and its inhibitor, hepatocyte activator inhibitor 1 (Hai1), are coexpressed in most epithelia and may make up a local signaling system that regulates epithelial behavior. We explored the role of Par2b in matriptase-dependent skin abnormalities in Hai1a-deficient zebrafish embryos. We s ...[more]

PMID: 29301867

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Project description:Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell-cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.

Project description:Epithelial tissues maintain homeostasis through the continual addition and removal of cells. Homeostasis is necessary for epithelia to maintain barrier function and prevent the accumulation of defective cells. Unfit, excess, and dying cells can be removed from epithelia by the process of extrusion. Controlled cell death and extrusion in the epithelium of the larval zebrafish tail fin coincides with oscillation of cell area, both in the extruding cell and its neighbors. Both cell-autonomous and non-autonomous factors have been proposed to contribute to extrusion but have been challenging to test by experimental approaches. Here we develop a dynamic cell-based biophysical model that recapitulates the process of oscillatory cell extrusion to test and compare the relative contributions of these factors. Our model incorporates the mechanical properties of individual epithelial cells in a two-dimensional simulation as repelling active particles. The area of cells destined to extrude oscillates with varying durations or amplitudes, decreasing their mechanical contribution to the epithelium and surrendering their space to surrounding cells. Quantitative variations in cell shape and size during extrusion are visualized by a hybrid weighted Voronoi tessellation technique that renders individual cell mechanical properties directly into an epithelial sheet. To explore the role of autonomous and non-autonomous mechanics, we vary the biophysical properties and behaviors of extruding cells and neighbors such as the period and amplitude of repulsive forces, cell density, and tissue viscosity. Our data suggest that cell autonomous processes are major contributors to the dynamics of extrusion, with the mechanical microenvironment providing a less pronounced contribution. Our computational model based on in vivo data serves as a tool to provide insights into the cellular dynamics and localized changes in mechanics that promote elimination of unwanted cells from epithelia during homeostatic tissue maintenance.

Dataset Information

Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia.

Publications

Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia.

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