The body as a machine is often used metaphorically for describing the raw brutality of physical performance in contrast to the sensitive biological processes that control the minutest processes in cells. By studying the mechanical forces involved in cell-to-cell contacts, researchers have now revealed fundamentally different strategies that cells use to move at the single-cell level compared with when they are within cell populations. The new study proposes a new mechanism to understand how cells migrate during wound healing and the collective invasion of cancer cells.
The first time almost seems like magic. You apply a dressing to a severe wound, and when you remove it later, the skin is almost like new. For most people, wound healing is a completely natural phenomenon. If you explore the underlying processes, however, you discover a complicated balance and interaction between the physical forces between the cells and the biochemical processes inside the cells. Researchers have now studied in detail the mechanisms of cell motion and coordination to improve understanding of the processes of wound healing, how cancer cells invade and human development.
“Cells behave very differently as single cells and within cell communities. Individually, cells exhibit contractile behaviour, like a worm that contracts, whereas communities of cells are controlled by extensile forces, corresponding to the worm stretching out again. By measuring the response mechanical forces that cells generate we can observe a switching between the two mechanisms and at the same time see relocation of proteins we know are involved in binding cells together and that often change in cancer,” explains Amin Doostmohammadi, Assistant Professor, Niels Bohr Institute, University of Copenhagen.
Cells find their way back
The ability of cells to self-organize, migrate and evolve depends crucially on the interaction between the cell–cell matrix and cell–cell interaction, which controls various phenomena, including tissue morphogenesis, wound healing and tumour progression. In an international collaboration between scientists in Denmark, UK, France, Australia, and Singapore, led by Amin Doostmohammadi at the Niels Bohr Institute wanted to understand what makes the systems develop differently.
“Cells are active systems that constantly move away from thermal equilibrium, converting chemical energy into motion. When we isolate individual cells in the laboratory, the cells generate contractile force dipoles: the resulting forces come from contractions in cell skeleton: the poles approaching each other or contracting as a result of the movement of specific proteins. Something similar would also be expected to happen with multicellular layers, but we found that this depends on the cell type,” says Amin Doostmohammadi.
Cells of a connective tissue such as fibroblast exhibit contractile forces, whereas epithelial layers such as kidney cells or breast cancer cells exhibit extensile behaviour. The researchers therefore asked what might happen if the two types were mixed together. Would the forces cancel each other out or would one cell type affect the other?
“When we mixed the contractile and extensile cells together, we found a quite fascinating phenomenon: as the cells assembled, they slowly joined up with cells of the same type. So the differences in cell activity made the cells sort themselves into mixtures – something we imagine is a generic mechanism for forming patterns inside the body during organ formation and wound healing,” explains Amin Doostmohammadi.
Mechanical wound healing
Combining extensive experimental studies and computer modelling enabled the researchers to reveal which internal changes in the cells lead to the shift from the contractile to the extensile state and vice versa. The protein E-cadherin plays a significant role. When the researchers inactivated the gene encoding E-cadherin using CRISPR-Cas9, the cells switched from extensile to contractile.
“This is like flipping a switch, and voltage builds up between the cellular membrane and the liquid substrate inside. This in turn affects the actin stress fibres and leads to a whole range of mechanical and biological changes inside the cell. Similarly, the cell can be mechanically influenced externally, creating the same biological changes internally,” says Amin Doostmohammadi.
The researchers hope that understanding the mechanical basis of cell migration can be used to increase cells’ ability to heal wounds. However, the new findings could also be very useful in relation to the development of cancer. For years, cancer researchers have been very interested in E-cadherin, since the lack of E-cadherin has been linked to the development of cancer.
“This combined theory-experiment study has enabled us to begin to understand the mechanisms much better, such as which internal biochemical signals are activated by mechanical loads. Not only this is a strong toolbox for predicting how tissue develops healthily, but similarly it helps to understand what happens when things go wrong, for example in cancer, in which some cells break out of seemingly healthy tissue and begin to create tumours and, even worse, metastasize. If we can decode this mechanism, we may also be able to help with healing,” concludes Amin Doostmohammadi.
