Paradigm shift in the field of mechanobiology: surprising finding about cells

Scientists have discovered that cells have two distinct mechanisms for responding to different ranges of forces.

Research carried out at the National Center for Cardiovascular Research (CNIC), in Spain, may mean a paradigm shift in the field of mechanobiology, as it reveals that cells have two different mechanisms to respond to different ranges of forces, mediated by tiny dimples on its surface (caveolae) or large depressions, sinkholes.

The new study resolves controversies in this field, as pointed out by Miguel Ángel del Pozo, coordinator of the research and head of the Mechanoadaptation and Caveolae Biology group at the CNIC. Del Pozo also clarifies that the role of caveolae is essential in tissues that are subjected to great mechanical forces (such as muscle, heart, vessels, and adipose tissue), while that of sinkholes would be relevant to respond to low or medium forces.

This information can lead to reinterpretations of pathological processes such as atherosclerosis (something that this group of experts is currently investigating), tumor progression or neurodegenerative diseases, where mechanobiology is helping to clarify different aspects.

Proof of this is the recent international recognition in this field: the 2021 Nobel Prize in Medicine, awarded to David Julius and Ardem Patapoutian, for temperature and touch receptors (mechanical), or the 2022 Lasker Awards, awarded to Richard O. Hynes, Erkki Ruoslahti, and Timothy A. Springer, for integrins, mediators of the strength of cell adhesion to the matrix.

Cells, the researchers explain, are constantly subjected to mechanical forces of different types and intensity from their microenvironment, such as blood flow, muscle contractions or stretches, etc. To adapt their functioning to these stimuli, evolution has endowed them with mechanisms capable of “feeling” or detecting different forms of forces.

Among all the cellular structures with this capacity, the best known, says Miguel Ángel del Pozo, are the caveolae, ‘small caves’ in Latin. “They are tiny invaginations of the plasma membrane (the outer covering of cells), present in many cell types, which detect mechanical stimuli by modifying their geometry: they flatten when cells swell or undergo stretching (something similar to what what happens with wrinkles in a dress); and they re-form and clump together when the cell membrane is relaxed.”

These changes in turn, adds Dr. Del Pozo, “modulate networks of biochemical signals in the cell, in such a way that caveolae are not only mechanical adapters, but also transducers of mechanical information.”

Therefore, explains Fidel-Nicolás Lolo, leader of the research together with Dr. Del Pozo, “they are able to ‘read’ physics and translate it into cellular chemistry, allowing cells to adequately adapt their functioning to environmental demands.” However, he continues, “before this work, it was not clear if complete invagination is necessary for this process or if one of its parts, mainly caveolin-1 and cavina-1, is sufficient.”

To try to resolve this doubt, the CNIC researchers initially established a collaboration with Pere Roca-Cusachs, a biophysicist from the University of Barcelona (UB), to try to elucidate which component is the mechanical sensor and which the signal transducer.

The results of these experiments, together with many other biophysical measurements, carried out in collaboration with numerous national and international laboratories led by Jochen Guck (Max Planck Institute of Germany), Daniel Navajas and Xavier Trepat (IBEC, Barcelona) and Christophe Lamaze (Curie University I, Paris, France), among others, allowed us to demonstrate that cells that only expressed caveolin-1 -in the absence of cavin-1- were capable of allowing a mechanical response similar to cells with caveolae.

Surprised by this discovery, which challenged the leading role of caveolae in mechanobiology, the CNIC researchers tried to determine the functional difference between caveolae and the isolated role of caveolin-1, “which was not an easy task”, comments Dr. Fidel Lolo.

Dr. Del Pozo acknowledges that “sometimes in science, the Eureka moment arises from trying something different from the conventional… Thus, we undertook a stimulating intellectual collaboration with the mathematicians Marino Arroyo and Nikhil Walani, who using computer simulations predicted a differential response to the ‘tightening’ of the membrane: while caveolae only respond above a certain threshold of relatively high forces, caveolin-1 is capable of forming invaginations with a different geometry and capable of ‘feeling’ and flattening when receiving low forces and stockings”.

Encouraged by these theoretical results, comments Dr. Lolo, “we collaborated with Britta Qualmann, Michael Kessels and Eric Seemann, pioneers in a novel electron microscopy technique at the University of Jenna (Germany), who finally managed to find the conjectured invaginations formed by caveolin-1 in the absence of caveolae”.

The CNIC researchers coined the term “sinkhole” to name these new invaginations, given their resemblance to the depressions of karstic phenomena, the famous Gran Sinkhole of Atapuerca, the tomb of Homo Antecessor north of Burgos in Spain.

Cells use two mechanisms to detect force: a gradual and progressive one, mediated by recently identified large depressions in the membrane called sinkholes (left); the other abrupt, activated from a certain threshold, and mediated by tiny invaginations of the membrane called caveolae (right). (Image: CNIC)

The caveolar response is an on-off switch, which is only activated from a high force threshold, and requires minutes. However, the new structures respond gradually, continuously and immediately (seconds) to smaller ranges of force in crescendo.

On the other hand, Dr. Lolo suggests that “sinkholes could be especially important in cells that do not have caveolae (such as lymphocytes or neurons), but that do express certain levels of caveolin-1, so that their physiology would be adapted to respond to more subtle forces of the microenvironment in which these cell types live”.

Dr. del Pozo concludes that this finding would have been unthinkable without a multidisciplinary approach: “sometimes when you are lost in an investigation, modeling the phenomenon in question with the help of a mathematician, for example, can lead you to the Eureka moment!”.

The study is titled “Caveolin-1 dolines form a distinct and rapid caveolae-independent mechanoadaptation system”. And it has been published in the academic journal Nature Cell Biology. (Source: CNIC)