The first batch of results of the HexaTissue project was beyond the PI’s most optimistic expectations. The multi-scale structure of epithelia, which was inaccessible to previous theoretical approaches, being these either cell- or organism-resolved, emerged naturally within the new framework while combining multiple types of liquid crystal order — corresponding to different values of the integer p — with activity, that is the ability of generating forces. In particular, this construction highlighted the possibility that both nematic (i.e. p=2) and hexatic (i.e. p=6) could coexist at different length scales, with the former being dominant at the large and the former at the small scale. This prediction, named “hexanematic” order in the publications where it was reported, was confirmed by numerical simulations of two different cell-resolved model of epithelia — the so-called Voronoi model and Multi Phase-field Model — and, later, by a direct comparison with in vitro layers of Madin-Darby canine kidney cells (MDCK). The first experimental work, currently under review in Nature Physics, showed that the crossover between hexatic and nematic order occurred at a length scale corresponding to clusters of approximatively 20 cells. A follow-up experimental study — currently under review in Nature Communications — demonstrated that such a hexanematic crossover scale depends on the mechanical and biochemical properties of both the cells and the substrate, such as the cell density, the substate stiffness and the level of expression of adhesion proteins, such as E-cadherin. It was speculated — and it will next be investigated — that such a peculiar multi-scale organisation, as well as the possibility of tuning the hexanematic crossover scale, could be instrumental to the versatility of epithelial tissues and complement the complex set of singling pathways that cells have a their disposal to achieve biological functionality. For instance, collective cell migration in epithelia relies on both remodelling events at the small scale — such as cell intercalation and the rearrangement of multicellular rosettes — as well as large scale flows. Therefore, the underlying hexanematic multscagle organisation and the specific magnitude of the crossover scale are expected to have a profound impact on how the geometry of the environment affects the specific migration strategy. E.g. metastatic cells traveling through micron-sized channels in the extracellular matrix during cancer invasion will more likely rely on local hexatic-controlled remodelling events, whereas unconfined wound healing processes are more likely to leverage on system-wide nematic-driven collective flows.
