Possible roles of mechanical cell elimination intrinsic to growing tissues from the perspective of tissue growth efficiency and homeostasis

Abstract

Cell competition is a phenomenon originally described as the competition between cell populations with different genetic backgrounds; losing cells with lower fitness are eliminated. With the progress in identification of related molecules, some reports described the relevance of cell mechanics during elimination. Furthermore, recent live imaging studies have shown that even in tissues composed of genetically identical cells, a non-negligible number of cells are eliminated during growth. Thus, mechanical cell elimination (MCE) as a consequence of mechanical cellular interactions is an unavoidable event in growing tissues and a commonly observed phenomenon. Here, we studied MCE in a genetically-homogeneous tissue from the perspective of tissue growth efficiency and homeostasis. First, we propose two quantitative measures, cell and tissue fitness, to evaluate cellular competitiveness and tissue growth efficiency, respectively. By mechanical tissue simulation in a pure population where all cells have the same mechanical traits, we clarified the dependence of cell elimination rate or cell fitness on different mechanical/growth parameters. In particular, we found that geometrical (specifically, cell size) and mechanical (stress magnitude) heterogeneities are common determinants of the elimination rate. Based on these results, we propose possible mechanical feedback mechanisms that could improve tissue growth efficiency and density/stress homeostasis. Moreover, when cells with different mechanical traits are mixed (e.g., in the presence of phenotypic variation), we show that MCE could drive a drastic shift in cell trait distribution, thereby improving tissue growth efficiency through the selection of cellular traits, i.e. intra-tissue “evolution”. Along with the improvement of growth efficiency, cell density, stress state, and phenotype (mechanical traits) were also shown to be homogenized through growth. More theoretically, we propose a mathematical model that approximates cell competition dynamics, by which the time evolution of tissue fitness and cellular trait distribution can be predicted without directly simulating a cell-based mechanical model.

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

“…Growth differences can generate mechanical stress in and around fast-growing winners, leading to cell competition (Lee and Morishita, 2017; Mao et al, 2013; Shraiman, 2005; Vincent et al, 2013). Cell mixing and mechanical competition play key roles in Myc-based competition in the Drosophila pupal notum (Levayer et al, 2015).…”

Mechanical cell competition in heterogeneous epithelial tissues

“…In mathematical models of cell competition the classical hypothesis is that cells compete due to differences in their intrinsic proliferation rates. However, this may not be true and mathematical models have began to explore different mechanisms [19,48]. We will explore mechanical cell competition.…”

Single-cell approaches to cell competition: High-throughput imaging, machine learning and simulations

“…ODE based models tend to reduce the multi-variate parameters of cell competition to a single asymmetry parameter for the fitness of competition. Fitness asymmetry is sometimes modelled as the difference in growth rates in an ODE model [6,34]. Yet, many studies of cell competition have concluded that differential growth is not the only source of competition.…”

“…Vertex models have been widely used in epithelial monolayer modelling including cell sorting [45], germband extension [46], ventral furrow formation [47], cell division and tissue elongation [48], wound healing [49,50], as well as tumor growth [51]. Vertex models have been used in studies of mechanical cell competition [34], as well as to infer the role of local epithelial topology on mutant clone expansion [23]. Vertex models, however, have some key disadvantages, including the difficulty to model arbitrary cell shapes, isolated cells, or cell clusters.…”