Mechanical basis and topological routes to cell elimination

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    eLife assessment

    In this work, Monfared et al. construct a useful three-dimensional phase-field model for cell layers and use this to investigate the link of extrusion events to defects in cellular arrangement. The extension of existing 2D phase field models to three dimensions is an important contribution of this paper. Here the model is used to study the importance of cell-cell and cell-substrate interaction in extrusion from cell monolayers. Their claim that extrusion events can be distinctly linked to defects in nematic and hexatic orders in the monolayer need to be better justified to be fully convincing.

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Abstract

Cell layers eliminate unwanted cells through the extrusion process, which underlines healthy versus flawed tissue behaviors. Although several biochemical pathways have been identified, the underlying mechanical basis including the forces involved in cellular extrusion remains largely unexplored. Utilizing a phase-field model of a three-dimensional cell layer, we study the interplay of cell extrusion with cell–cell and cell–substrate interactions in a flat monolayer. Independent tuning of cell–cell versus cell–substrate adhesion forces reveals that extrusion events can be distinctly linked to defects in nematic and hexatic orders associated with cellular arrangements. Specifically, we show that by increasing relative cell–cell adhesion forces the cell monolayer can switch between the collective tendency towards fivefold, hexatic, disclinations relative to half-integer, nematic, defects for extruding a cell. We unify our findings by accessing three-dimensional mechanical stress fields to show that an extrusion event acts as a mechanism to relieve localized stress concentration.

Article activity feed

  1. eLife assessment

    In this work, Monfared et al. construct a useful three-dimensional phase-field model for cell layers and use this to investigate the link of extrusion events to defects in cellular arrangement. The extension of existing 2D phase field models to three dimensions is an important contribution of this paper. Here the model is used to study the importance of cell-cell and cell-substrate interaction in extrusion from cell monolayers. Their claim that extrusion events can be distinctly linked to defects in nematic and hexatic orders in the monolayer need to be better justified to be fully convincing.

  2. Reviewer #1 (Public Review):

    Monfared et al. construct a three-dimensional phase-field model of cell layers and use it to examine cellular extrusion by independently tuning cell-substrate and cell-cell adhesion. In line with earlier studies (in some of which some of the authors were involved), they find that extrusion is linked to topological defects in cellular arrangement and relieving stress.
    The authors claim that their development of the three-dimensional phase field model is crucial for understanding cell extrusion (which I agree with the authors is inherently three-dimensional). However, I don't think the data they currently present clearly demonstrate that the three-dimensional model adds significantly more to our understanding of extrusion events than earlier two-dimensional models.

    In the end, I think that the more important …

  3. Reviewer #2 (Public Review):

    The paper provides a natural extension of 2D multiphase field models for cell monolayers to 3D, addressing cell deformations, cell-cell interaction, cell-substrate interactions and active components for the cells. As known from 2D, the cell arrangement leads to positional (hexatic) defects and if the elongation of the cells is coarse-grained to define a global nematic order also to orientational (nematic) defects. These defects are characterized, see Figure 2. However, this is done in 2D and it remains unclear if the projected basal or apical side is considered in this figure and the following statistics. The authors identify correlations between orientational defects and extrusion events. In terms of positional defects such statistics seem not to be considered and the relation between positional defects and …

  4. Reviewer #3 (Public Review):

    In this paper, the authors studied the influence of topological defects on extrusion events using 3D multi-phase field simulations. By varying cell-cell and cell-substrate parameters, this study helps to better understand the influence of mechanical and geometrical parameters on cell extrusion and their linkage to topological defects.

    First the authors show that extrusion events and topological defects of nematic and hexatic order are typically found in their system, and then that extrusions occur, on average, at a distance of a few cell sizes from a + and - 1/2 defects. Next, the author analyse at extrusion events the temporal evolution of the local isotropic stress and the local out-of-plane shear stress, showing that near the instant of extrusion, the isotropic stresses relax and the shear stresses …

  5. Author Response:

    Reviewer #1 (Public Review):

    Monfared et al. construct a three-dimensional phase-field model of cell layers and use it to examine cellular extrusion by independently tuning cell-substrate and cell-cell adhesion. In line with earlier studies (in some of which some of the authors were involved), they find that extrusion is linked to topological defects in cellular arrangement and relieving stress.
    The authors claim that their development of the three-dimensional phase field model is crucial for understanding cell extrusion (which I agree with the authors is inherently three-dimensional). However, I don't think the data they currently present clearly demonstrate that the three-dimensional model adds significantly more to our understanding of extrusion events than earlier two-dimensional models.

    In the end, I think that …