The coordination of cell proliferation and migration in growing tissues is crucial in development and regeneration but remains poorly understood. Here, we find that, while expanding with an edge speed independent of initial conditions, millimeter-scale epithelial monolayers exhibit internal patterns of proliferation and migration that depend not on the current but on the initial tissue size, indicating memory effects. Specifically, the core of large tissues becomes very dense, almost quiescent, and ceases cell-cycle progression. In contrast, initially-smaller tissues develop a local minimum of cell density and a tissue-spanning vortex. To explain vortex formation, we propose an active polar fluid model with a feedback between cell polarization and tissue flow. Taken together, our findings suggest that expanding epithelia decouple their internal and edge regions, which enables robust expansion dynamics despite the presence of size- and history-dependent patterns in the tissue interior.
Keywords: MDCK cells; cell cycle; collective migration; developmental biology; epithelia; none; physics of living systems.
Cells do not exist in isolation. Instead, they form tissues, where individual cells make contact with their neighbors and form microscopic ‘architectures’. Epithelia are a type of tissue where cells are arranged in flat sheets, and are found in organs such as the lining of the kidney or the skin. Tissues need to grow, especially early in life. If tissues are damaged – for example, if the skin is cut or grazed – cells also need to divide (to create new healthy cells) and move as a group (to close the wound). Such coordinated motions result in cells exhibiting distinct group behaviors, similar to those observed within crowds of people or schools of fish. If coordination breaks down, problems can happen such as uncoordinated tissue growth seen in cancer. However, how cell movements are coordinated is still not fully understand. For example, researchers know that cells’ positions within a group can determine how they behave, meaning that even the same type of cell could behave differently at the edge or center of a tissue. This suggests that the initial size and shape of a tissue should influence its subsequent growth and behavior; however, the nature of this influence is still largely unknown. Heinrich et al. therefore wanted to determine the differences in the way larger and smaller tissues grow. Microscope imaging was used to track the growth of circular, artificial tissues made from single-layered sheets of dog kidney cells grown in the laboratory. Comparing how quickly the tissues expanded revealed that the area of tissue circles that started out smaller increased at a much faster rate than that of tissue circles that were larger to begin with. This turned out to be because the edges of the tissues grew at a constant speed, independent of their initial size or shape, but circles with a smaller area have a larger proportion of cells on their edges. The motions of the cells at the center of the tissues had no effect on how the edges of the tissue grew. A final observation was that the way tissues of a given size behaved depended on whether they had grown to be that size, or they started off that big. These results shed light on how groups of cells interact in growing tissues. In the future, this information could be used to predict how different tissues grow over time, potentially helping scientists engineer better artificial tissues or organs for transplantation.
© 2020, Heinrich et al.