Mechanical basis and topological routes to cell elimination

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.

Cell sorting by active forces in a phase-field model of cell monolayers

“…However, fluctuating polar forces 38 or active forces which act along cell–cell junctions 14 may be relevant, as may apical-basal asymmetry if a monolayer is modelled in three dimensions. 39…”

Short-range correlation of stress chains near solid-to-liquid transition in active monolayers

“…Activity in our study is owing to active polarity. The particular model we use is tuned directly by experiments [ 51 ] and specifically chosen given its success in representing cell motility by reproducing stress patterns around nematic defects [ 45 , 47 ]. In this vein, a recent study suggests that the active glassy dynamics are mute to the details of such a model [ 68 ].…”

“…where is the velocity of cell , represents mobility, is the free energy functional that stabilizes cell interface and includes mechanical properties such as cell stiffness ( ) as well as compressibility ( ), and puts a soft constraint on the cell volume [ 41 – 44 ] around . Additionally, the free energy comprises gradient contributions ( ) that account for, and distinguish between, cell–cell ( ) and cell–substrate ( ) adhesions, as introduced recently [ 45 ],…”

“…is the counterclockwise angle of cell polarity measured from e → x , F ^i pol = cos θ i , sin θ i , 0 and η is the Gaussian white noise with zero mean, unit variance, D r is rotational diffusivity, ΔΘ i is the angle between F ^i pol and T → i , with positive constant τ pol setting the alignment time scale between them (see electronic supplementary material for simulation parameters). Previously, this model was tuned directly against experiments [51] and specifically chosen given its success in reproducing stress fields around nematic defects [45,47].…”

Coexisting mechanisms of luminogenesis in pancreatic cancer-derived organoids

“… 55 This is in agreement with previously reported observations that Ki-67 expression, a marker for cell proliferation capability, decreased as organoids matured, disappearing first from the thick regions in the organoids cores, and persisting only in a few cells located in the buds. 8 While the parameters governing the side of elimination of epithelium cells (basal or apical) remain unclear at this stage, models considering the interplay between cell-cell- and cell-ECM-adhesion, 56 along with mechanosensitive responses 57 have proposed mechanical control hypotheses that could be tested in further studies.…”