Professor Benoît Ladoux co-leads the Cell Adhesion and Mechanics research group at the Institut Jacques Monod. He and his teams have been exploring the relatively uncharted territory of mechanobiology for a number of years. Read on to discover his vision of the mechanisms at work and the issues connected with the discipline.
Mechanobiology, a new scientific approach that puts cells under pressure
Although largely overlooked by scientific research throughout the 20th century, mechanobiology, which studies the influence of mechanical forces on biological tissues, has been on the rise in the last three decades. “For years, the emphasis was on biochemical processes. The role of mechanics in cell formation was long underestimated”, says Benoît. The original work on this topic dates back to the early 20th century with the 1917 publication of On Growth and Form by D’Arcy Thompson, a Scottish biologist. “He was one of the first to pay attention to plant and animal development processeses, and specifically to the effects of physical stress on cells.” Work on mechanobiology eventually took off in the 1980s, driven forward by pioneering research, as new scientific techniques made it possible to observe that mechanical forces exerted on cells and their environment have an influence on how cells form, migrate, interact and adhere to one another.
Formerly a researcher at Université Paris Diderot’s Matter and Complex Systems Laboratory, Benoît earned his stripes at the head of a team working on physics, biology and engineering. These days, he puts his interdisciplinary knowledge at work to explore mechanobiology at the Institut Jacques Monod. “Our Cell Adhesion and Mechanics research group is seeking to understand how the mechanical environment functions, its geometry, rigidity, and the forces exercised both by and on cells. In particular, we observe the behaviour of the epithelial cells that cover the external or internal surface of organs: they are squeezed tightly against one another and interact with each other largely through cell adhesion molecules”, he explains.
How mechanical signals influence the biological development of tissues and organs
One of the key principles studied by Benoît is “mechanotransduction”, which is the process whereby cells incorporate mechanical signals sent to them and convert them into biochemical signals. “It is a process that integrates all levels, from molecular to cell biology and tissue and organ development.”
At the level of the cell’s biology, interactions between cells or with their surrounding matrix are influenced by environmental mechanical stimuli. By cultivating cells on substrates of varying rigidity, researchers at the Institut Jacques Monod noticed that adhesion between cells varied. As Benoît explains: “When placed on an overly soft substrate, they slip and struggle to grip, which disrupts their internal structure. Conversely, adhesion is strengthened when cells are placed on a stiffer substrate. These changes in environment lead them to adjust their internal architecture and cytoskeleton in order to gain a hold and exert adequate forces”.
Repercussions are visible at the level of morphogenesis, which is the process that gives an organism its form: “The link that binds cells together partly accounts for tissue and organism properties. The mechanical signals that modify cell formation and adhesion therefore influence the development of tissue structure. One of our challenges today is to understand how external mechanical constraints spread through the cytoplasm to the cell nucleus to activate an appropriate genetic programme”. Recent research has shown that mechanical forces guide the embryonic development of some organisms. In 2011, Michel Labouesse and his team showed that contractions in the muscle cells of C. Elegans, a transparent and free-living roundworm about one millimetre long, are transmitted to epithelial cells, enabling the organism to elongate. This offers proof that mechanobiology impacts organism development.
From scarring to cancer prevention, how mechanobiology breathes new life into a wide scope of research
As a result, mechanobiology is revolutionising numerous fields of research, from scarring to anti-cancer treatments.
In the case of scarring, mechanobiology helps to facilitate and accelerate the closure of chronic or serious wounds. “Our work at Singapore’s Mechanobiology Institute has shown, for example, that if the underlying matrix is damaged, interfering with the adhesion of cells to their environment, the contraction of the cell’s “purse string” around the zone makes it possible to form a layer of cells suspended above the wound, enabling the scar to close completely.”
In anti-cancer treatments, especially for epithelial tumours, cells respond to mechanical forces and changes in the environment, such as rigidification, to communicate and modify their cohesion. “Understanding these changes is crucial to studying the invasion of tumour cells and thus to combatting certain tumours”, says Benoît.
The great challenge of understanding the relationship between cells and mechanical forces
“For every research avenue it opens up, mechanobiology raises a question to answer”, Benoît argues. One question in particular stands out for him: “Understanding how mechanical constraints spread from the surrounding environment to the nucleus. Mechanical signals do not follow a unidirectional path from exterior to interior because cells react and respond to these signals. In other words, exchanges go in both directions. An improved understanding of these meeting points between physics and biology is crucial to continuing in this new field of research”.