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May 3, 2021

from the University of Geneva

In materials physics, it is of central interest to understand how systems interact across the interfaces that separate them. But can physical models clarify similar concepts in living systems like cells? Physicists at the University of Geneva (UNIGE), in collaboration with the University of Zurich (UZH), examined the framework of disordered elastic systems to investigate the process of wound healing – the proliferation of cell fronts that eventually combine to close a lesion. Their study identified the scales of dominant interactions between cells that determine this process. The results, published in the journal Scientific Reports, enable a better analysis of the behavior of the cell front, both with regard to wound healing and tumor development. In the future, this approach could offer personalized diagnostics to classify cancers, better target their treatment, and identify new pharmacological targets for transplantation.

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By focusing on the macroscopic properties of large data sets, statistical physics enables an overview of the system behavior to be obtained regardless of its specific microscopic character. This approach is applied to biological elements such as the cell fronts adjacent to a wound and makes it possible to identify the various interactions that play a crucial role in the growth, differentiation and healing of tissue, but above all their hierarchy on the various scales observed to highlight. Patrycja Paruch, Professor at the Institute for Quantum Matter Physics of the UNIGE Faculty of Natural Sciences, explains: “For the invasion of cancerous tumors or in the case of a wound, the proliferation of the cell front is crucial, but the speed and morphology of the front is high. However, we believe that only few dominant interactions during this process define the dynamics and shape – smooth or rough, for example – of the edge of the cell colony.Experimental observations across multiple length scales to extract general behaviors can allow us to identify these interactions in healthy tissue and diagnose the level at which pathological changes can occur in order to combat them. This is where statistical physics comes into play. “

In this multidisciplinary study, the UNIGE physicists worked together with the team of Professor Steven Brown from UZH. Using rat epithelial cells, they established flat colonies (2D) in which the cells grow around a silicone insert and are then removed to mimic an open lesion. The cell fronts then multiply to fill the opening and heal the tissue. “We reproduced five possible scenarios by ‘hindering’ the cells in different ways to see what effect this has on wound healing, that is, on the speed and roughness of the cell front,” explains Guillaume Rapin, a researcher on the team by Patrycja Paruch. The idea is to see what happens in normal healthy tissue or when processes such as cell division and communication between neighboring cells are inhibited, when cell mobility is reduced or when cells are permanently pharmacologically stimulated. “We took 300 images every four hours for about 80 hours, which allowed us to observe the proliferating cell fronts on very different scales,” continues Guillaume Rapin. “By applying high-performance computational techniques, we were able to compare our experimental observations with the results of numerical simulations,” adds Nirvana Caballero, another researcher in Patrycja Paruch’s team.

The scientists observed two different roughness states: at less than 15 micrometers, below the size of a single cell and between 80 and 200 microns when multiple cells are involved. “We have analyzed how the roughness exponent evolves over time to reach its natural dynamic equilibrium, depending on the pharmacochemical conditions we have placed on the cells and how this roughness depends on the scale we are looking at , is increasing, “emphasizes Nirvana Caballero. “In a system with a single dominant interaction, we expect the same roughness exponent on all scales. Here we see a changing roughness when we look at the scale of one cell or of 10 cells.”

The teams in Geneva and Zurich showed only slight deviations in the roughness exponent below 15 micrometers, regardless of the conditions imposed on the cell fronts. On the other hand, they found that between 80 and 150 micrometers the roughness is changed by all pharmacological inhibitors, which significantly reduces the roughness exponent. In addition, they observed that the rate of proliferation varied widely between different pharmacochemical conditions, slowed down when cell division and motility were inhibited, and accelerated when cells were stimulated. “Surprisingly, the fastest rate of proliferation was achieved when gap-junction communication between cells was blocked,” says Guillaume Rapin. This observation suggests that such communication can be used in future therapies to either promote the healing of burns or wounds or to slow the invasion of cancerous tumors.

These results show that medium-sized interactions play a crucial role the determination of the healthy proliferation of a cell front. “We now know at what scale biologists should look for problematic behavior in cell fronts that can lead to the development of tumors,” says Nirvana Caballero. Now scientists can focus on these key lengths to examine the fronts of tumor cells and compare their pathological interactions directly with those of healthy cells.

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Related title :
A Physical Perspective on Wound Healing
Using the statistical physics approach to wound healing