In materials physics, understanding how systems interact across the interfaces that separate them is of central interest. But can physical models clarify similar concepts in living systems, such as cells? Physicists from the University of Geneva (UNIGE), in collaboration with the University of Zurich (UZH), used the framework of disordered elastic systems to study the process of wound healing – the proliferation of cell fronts that eventually collapse. join to close a lesion. Their study identified the scales of the dominant interactions between cells that determine this process. The results, published in the journal Scientific reports, will allow a better analysis of the behavior of the cell front, both in terms of wound healing and tumor development. In the future, this approach could offer personalized diagnostics to classify cancers and better target their treatment, and identify new pharmacological targets for transplantation.
By focusing on the macroscopic properties of large data sets, statistical physics makes it possible to extract an overview of the behavior of the system regardless of its specific microscopic character. Applied to biological elements, such as the cell fronts bordering a wound, this approach makes it possible to identify the different interactions that play a determining role during tissue growth, differentiation and healing, but above all to highlight their hierarchy at the edges. different scales observed. . Patrycja Paruch, professor in the Department of Quantum Matter Physics at the Faculty of Sciences of UNIGE, explains: “For the invasion of cancerous tumors, or in the event of a wound, the proliferation of the cell front is crucial, but the speed and the morphology of the forehead are very important. However, we believe that only a few dominant interactions during this process will define the dynamics and shape – smooth or rough, for example – of the edge of the cell colony. Experimental observations on multiple length scales to extract general behaviors can allow us to identify these interactions in healthy tissue and diagnose at what level pathological changes may occur, to help combat them. This is where statistical physics comes in. “
The many scales of wound healing
In this multidisciplinary study, physicists from UNIGE collaborated with the team of Professor Steven Brown from UZH. Using rat epithelial cells, they established flat (2D) colonies in which cells grow around a silicone insert, then removed to mimic an open lesion. The cell fronts then proliferate to fill the opening and heal the tissue. “We reproduced five possible scenarios by ‘disabling’ the cells in different ways, in order to see what impact this has on wound healing, that is to say on the speed and roughness of the cell front,” explains Guillaume. Rapin, researcher in Patrycja Paruch’s team. . 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 continuously pharmacologically stimulated. “We took some 300 images every four hours for about 80 hours, which allowed us to observe the proliferating cell fronts at very different scales,” continues Guillaume Rapin. “By applying high-performance calculation 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.
Zoom out for better effect
Scientists observed two distinct roughness regimes: within 15 micrometers, below the size of a single cell, and between 80 and 200 micrometers, when multiple cells are involved. “We analyzed how the roughness exponent changes over time to reach its natural dynamic balance, depending on the pharmacochemical conditions that we have imposed on the cells, and how this roughness increases depending on the scale at which we are looking”, emphasizes Nirvana Caballero. “In a system with a single dominant interaction, we would expect to see the same roughness exponent at all scales. Here we see changing roughness if we look at the scale of one cell or ten cells.”
The Geneva and Zurich teams revealed only minor variations 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 altered by all pharmacological inhibitors, significantly reducing the roughness exponent. In addition, they observed that the rate of proliferation varied considerably between different pharmacochemical conditions, slowing down when cell division and motility were inhibited, and accelerating when cells were stimulated. “More surprisingly, the fastest proliferation speed was obtained when communication between junction cells between cells was blocked,” explains Guillaume Rapin. This observation suggests that such communication could be targeted in future therapies, either to promote healing of burns or wounds, or to slow the invasion of cancerous tumors.
These results show that medium-scale interactions play a crucial role in determining the healthy proliferation of a cell front. “We now know at what scale biologists should look for problematic behavior of cell fronts, which can lead to the development of tumors,” says Nirvana Caballero. Now scientists will be able to focus on these key length scales to probe the fronts of tumor cells and directly compare their pathological interactions with those of healthy cells.
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