Study reveals how force dynamics affect cells and living tissue

Researchers led by Pere Roca-Cusachs from the Institute for Bioengineering of Catalonia (IBEC) are discovering how force dynamics affect cells and living tissue. The results provide insight into the critical mechanical processes that take place in various diseases such as cancer.

From the vocal cords that generate our voice to our heartbeat, our body cells are constantly exposed to mechanical forces that constantly change their response to these stimuli and regulate vital processes, both in healthy people and in diseases such as cancer. Despite their importance, however, we largely do not know how cells perceive these forces and react to them.

Now an international team is being jointly led by researcher Pere Roca-Cusachs of the Institute for Bioengineering of Catalonia (IBEC) and Isaac Almendros, researcher at the Respiratory Diseases Networking Biomedical Research Center (CIBERES) and IDIBAPS, both professors of the Faculty of Medicine and Health Sciences from the University of Barcelona (UB) has proven that the mechanical sensitivity of cells determines the speed at which force is applied, i.e. the speed at which force is applied. The paper was published in the renowned journal Nature communication and shows for the first time in vivo the predictions of the “molecular coupling” model.

These results open the door to a better understanding of how cancerous tumors multiply and how the heart, vocal cords, or the respiratory system react to the ever-changing forces to which they are repeatedly exposed.

A constant cellular “push and pull”:

The researchers observed that there are two responses to the force applied to a cell using cutting edge techniques such as atomic force microscopy (AFM) or so-called “optical tweezers”.

On the one hand, the cytoskeleton, the dense fiber network (mainly actin), which among other things has the function of maintaining the shape and structure of the cell, is strengthened when the cell is subjected to moderate force. The cell is able to perceive and react to mechanical forces, and the strengthening of the cytoskeleton leads to a stiffening of the cell and to the localization of the YAP protein in the cell nucleus. In this case, the YAP protein controls and activates genes associated with cancer development.

On the other hand, if the rate of force applied is repeatedly applied above a certain value, an opposite effect occurs; the cell no longer feels the mechanical forces. In other words, instead of stiffening the cytoskeleton and the cell, the cytoskeleton is partially broken down, causing the cell to soften.

As with the stretching and shrinking of chewing gum, we have controlled cells and subjected them to precise various forces, and we have seen that the rate at which the force is exerted is of the utmost importance in determining cellular response. “

Ion Andreu (IBEC), co-lead author of the study

A model confirmed by in vivo experiments:

To understand how the strengthening and softening effects of the cytoskeleton are related, the researchers developed a computer model that shows the effects of progressive force on the cytoskeleton and the “couplings” (proteins involved in binding the cell to the substrate, such as z like Talin and Integrin). These “clutches” are somewhat similar to the clutch on a car in that they tighten the mechanical connection between the engine and wheels, which is why the model is known as a “molecular clutch”.

Next, the scientists carried out experiments on laboratory rats to prove that the results observed on individual cells also occur in whole organs in vivo. To do this, the researchers examined the lungs, which are mechanically stretched in a natural, cyclical manner while breathing. In particular, the two lungs were ventilated at different rates, with one lung filling and deflating faster (hyperventilation) and the other slower while maintaining a normal overall ventilation rate.

After analyzing and comparing cells from both lungs, they found that the YAP protein increased its nuclear localization only in cells from the lungs that had undergone hyperventilation. This increase in YAP in in vivo samples caused by the “cellular tug of war” was similar to that of proliferating cancerous tumors.

“At the organ level, our results show the role of the rate of force application in the transduction of the ventilation-induced mechanical signal in the lungs,” says Bryan Falcones (IBEC-UB), co-lead author of the study.

The paper describes a mechanism by which cells react not only to direct forces, but also to other passive mechanical stimuli, such as the stiffness of the substrate on which they are located. The results provide an insight into how a priori opposing phenomena, such as the strengthening and softening of the cytoskeleton, are associated with the control of cell mechanics and can react specifically to different situations.