Using the framework of disordered elastic systems, physicists at the University of Geneva (UNIGE), in collaboration with the University of Zurich (UZH), have studied the process of wound healing. They identified the scales of the dominant interactions between cells which determine this process.
The study will allow better analysis of cell front behavior in terms of both wound healing and tumor development. It could also offer personalized diagnostics to classify cancers and better target their treatment.
Statistical physics mainly focuses on large datasets’ macroscopic properties, allowing extraction of an overview of system behavior independent of its specific microscopic character. Usually applies to biological elements, this approach helps in identifying several interactions which play a defining role during tissue growth, differentiation, and healing. What’s more, it could also shed light on their hierarchy at the different scales observed.
Patrycja Paruch, professor in the Department of Quantum Matter Physics at the UNIGE Faculty of Science, explains: “For cancer tumor invasion, or in the event of a wound, cell front proliferation is crucial, but the speed and morphology of the front is highly variable. However, we believe that only a few dominant interactions during this process will define the dynamics and the shape – smooth or rough, for example – of the cell colony edge. Experimental observations across multiple length scales to extract general behaviors can allow us to identify these interactions in healthy tissue and diagnose at what level pathological changes can help combat them. This is where statistical physics comes in.”
In this study, scientists used rat epithelial cells to establish flat colonies (2D) in which the cells grow around a silicone insert. They were then subsequently removed to mimic an open lesion. The cell fronts then proliferate to fill the opening and heal the tissue.
Guillaume Rapin, a researcher in Patrycja Paruch’s team, said, “We reproduced five possible scenarios by ‘handicapping’ the cells in today, to see what impact this has on wound healing, i.e. on the speed and roughness of the cell front. 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 some 300 images every four hours for about 80 hours, which allowed us to observe the proliferating cell fronts at very different scales.”
Nirvana Caballero, another researcher in Patrycja Paruch’s team, said, “By applying high-performance computational techniques, we were able to compare our experimental observations with the results of numerical simulations.”
Scientists discovered two different roughness regimes: at less than 15 micrometers, below the size of a single cell, and between 80 and 200 micrometers when several cells are involved.
Nirvana Caballero said, “We have analyzed how the roughness exponent evolves over time to reach its natural dynamic equilibrium, depending on the pharmacochemical conditions we have imposed on the cells, and how this roughness increases depending on the scale at which we look. In a system with a single dominant interaction, we expect to see the same roughness exponent at all scales. Here, we see a changing roughness if we look at the scale of one cell of ten cells.”
There were some minor variations in the roughness exponent below 15 micrometers. 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. Moreover, they observed that proliferation speed varied significantly between the different pharmacochemical conditions, slowing when cell division and motility were inhibited and accelerating when cells were stimulated.
Guillaume Rapin said, “More surprisingly, the fastest proliferation speed was achieved when gap-junction communication between cells was blocked. This observation suggests that such communication may be targeted in future therapies to promote healing of burns or wounds or to slow cancer tumor invasion.”
Nirvana Caballero said, “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. Now scientists will be able to focus on these key length scales to probe tumor cells fronts, and directly compare their pathological interactions with this of healthy cells.”
- Rapin, G., Caballero, N., Gaponenko, I. et al. Roughness and dynamics of proliferating cell fronts as a probe of cell-cell interactions. Sci Rep 11, 8869 (2021). DOI: 10.1038/s41598-021-86684-3