Shape independent fluidisation in epithelial monolayers

Background: 

Epithelial tissues line the surface of our organs and are composed of confluent, closely packed cells. As such, epithelial cells show interesting properties such as jamming/unjamming, important for embryonic development, wound healing, cancer metastasis etc.

The jamming-unjamming transition in epithelia has been shown to be dictated by cell shape – elongated cells can easily change shape without significantly changing their perimeter or area, and thus drive the unjamming transition. In contrast, rounded cells display less shape variability and are more jammed.

Cell shape is controlled by different parameters including cell-cell adhesion strength: higher strengths energetically favour more cell-cell surface contact and thus support elongated cells with lowered line tension and unjamming. Parameters such as line tension and traction are also associated with tissue fluidity. For instance, unjamming is generally associated with higher traction and lower line tension.

In this preprint, however, the authors observed fluidisation when cell-cell adhesions were weakened, without any change in cell shape. To explain this, they considered the opposing effects of cell-cell adhesions on tissue dynamics- While it is known that reduced cell-cell adhesions increases line tension and supports jamming, the authors also considered the decreased friction with reduced cell adhesions, which promotes unjamming.

Key findings:

Shape independent fluidisation in epithelial monolayer when cell-cell adhesions are reduced:

Epithelial monolayers can undergo a fluid transition without elongating in cell shape when cell-cell adhesion strength is decreased by DECMA (Antibody) or EGTA (Calcium chelator). Cell density was kept constant by inhibiting cell division, to avoid the confounding effect of cell shape changing with density.

Reduced cell-cell adhesions does not change traction or line tension significantly:

The authors then checked if reduced line tension or increased traction could explain the fluid transition and performed traction force microscopy and laser ablation. However, there was no significant difference in the traction or line tension with DECMA. Although EGTA showed reduced traction associated with jamming, the tissue was still unjammed, suggesting the effect of EGTA on cell-cell adhesion outweighed its effect on traction.

Vertex model with viscous drag between cells predicts shape independent fluidisation with reduced adhesions:

As per the conventional vertex model, increased adhesions would increase cell-cell contacts and unjam the tissue- this was in line with previous experimental studies that showed unjamming with increased cell-cell adhesions (Cai et al., Malinverno et al., Lemahieu et al.  )  But the experimental observation in this preprint showed that reducing adhesions also unjammed the tissue. To explain this, the authors considered the dynamics of increased adhesions- when cells with higher cellular adhesion strength move, they encounter more viscous drag. Thus, higher adhesions would on the one hand increase drag between cells to jam the tissue, and on the other hand decrease line tension to unjam the tissue.

When they incorporated friction between cells in in their extended vertex model by adding a drag force related to cell-cell adhesions, the model predicted fluidisation with decreased adhesions, in line with the experimental results.

What I like about this preprint:

I was intrigued by this preprint because it showed that reducing cell-cell adhesions fluidises the tissue, because I have seen other studies where increasing cell adhesions also fluidised the tissue. It challenges the previous notion that jamming-unjamming transition is always accompanied by cell shape changes. It also adds a physically motivated extension to the vertex model by introducing adhesion mediated viscous drag, expanding our understanding of how cellular adhesions control tissue-level dynamics. Practically, this has implications for how we interpret cell shape measurements – a tissue may be dynamically fluid even while appearing geometrically “jammed” by conventional shape-index metrics.

Questions:

1. It is surprising that cell shapes and line tensions do not change when adhesion is reduced, and an explanation for this would be helpful. It is expected that with reduced adhesion strength, cells would reduce contact with their neighbors and thus be more rounded.
2. Although the model considers the opposing effects of line tension and viscous drag changes with changing adhesion strength on fluidity, experimentally, the line tension does not change when cell-adhesions are lowered, which is confusing.

Future directions:

1. Although the competition between viscous drag and adhesion energy in controlling tissue dynamics mediated by adhesion changes is clear from the extended vertex model, experimental evidence for the same would be more convincing. For instance, by modulating the components of adherens junctions (Catenins, for example) that connect it with the actin cytoskeleton may only increase the cell-cell adhesion mediated viscous drag without changing the associated line tension. Conversely, drugs that reduce contractility and thus cortical actin, may provide a way to modulate line tension independent of viscous drag.
2. It may be possible that due to junctional maturation at high density (Garcia et al.), cell shape is buffered by active cytoskeletal mechanisms at high density, which may not be the case in low density or non-confluent monolayers, and may be worth checking.

Tags: cellular adhesions, epithelial monolayers, mechanobiology, unjamming transition

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