A mechanical route to cell death

13 April 2017


By exploiting analogies to ‘active’ liquid crystals Oxford theoretical physicists have contributed to discovering a mechanical mechanism controlling the extrusion of dying cells from layers of tissue.

The removal of cells from a tissue occurs regularly. Not only are damaged or dying cells removed, but the process of cell extrusion can prevent regions from becoming overcrowded. This is particularly important not only during developmental processes when tissues and organs are being formed, but also in diseases such as cancer, when tumors grow uncontrollably. Despite the importance of cell extrusion in development and aging, as well as the pathological importance in cancer progression, the cues that flag a cell for removal were poorly understood.

Now, by studying single-layers of epithelial cells grown in the lab, and comparing to numerical models, Amin Doostmohammadi and Julia Yeomans from Oxford’s Rudolf Peierls Centre for Theoretical Physics, together with colleagues from the Mechanobiology Institute, National University of Singapore, Institut Jacques Monod, CNRS and University Paris Diderot (France), and Institut Curie (France) have found that a major factor driving cell death and removal relies on the physical arrangement of cells in the surrounding cell layer. In particular, the appearance of defects in the cellular patterns of epithelial layers promotes cell death and elimination from the tissues.

There are several examples in nature where a molecule or cell type aligns in a defined manner. Bacterial colonies, fat molecules, and even internal components of the cell, are just a few examples. A well-known example is liquid crystals, a state of matter between a solid and a liquid, which can consist of rod-shaped molecules. Under certain conditions, these molecules can align along a preferential orientation that can be altered by electric, magnetic fields or temperature. This phenomenon is particularly well-known since it is exploited in technologies such as liquid crystal displays. The starting point of this study was to show how the behavior of the cell sheet was analogous to ‘active’ liquid crystals.

Following this analogy, the team observed the emergence of topological defects, which caused the cells to realign so that they resembled a comet. In a liquid crystal display, such realignments of the molecules merely degrade the optical properties of the material. However, in an epithelial sheet, such changes in the pattern can mean life or death for the cells involved. Remarkably, it was after this cell realignment that cells near the head of the ‘comet pattern’ died and were removed from the surrounding tissue.

The emergence of topological defects lead to cell death and extrusion

To further investigate the relationship between cell death and topological defects, the scientists examined the forces being generated around the areas of cell misalignment. They found that compressive force concentrated at the head of the comet pattern. This force generated over an hour prior to cell extrusion, and was sufficient to trigger cell death at topological defects.

Tissue engineering and regenerative medicine requires scientists to carefully control cell growth and tissue development in a lab. The findings presented in this work are an important step towards achieving this. Indeed, the researchers successfully controlled how cells aligned by introducing shapes in areas where the cells grew that mimicked the topological defects associated with cell death and extrusion. This allowed them to pinpoint where in the cell sheet extrusion would occur.

These discoveries provide a significant step forward in our understanding of how the physical microenvironment plays a role in tissue development, and provides new approaches with which researchers can control, analyze and study cell growth and death.

The work has been published in Nature 544, 212-216

Topological defects in epithelia govern cell death and extrusion

Thuan Beng Saw, Amin Doostmohammadi, Vincent Nier, Leyla Kocgozlu, Sumesh Thampi, Yusuke Toyama, Philippe Marcq, Chwee Teck Lim, Julia M Yeomans, Benoit Ladoux