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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.

SUBMITTER: Lee SW

PROVIDER: S-EPMC5547694 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Project description:A key feature of living tissues is their capacity to remodel and grow in response to environmental cues. Within continuum mechanics, this process can be captured with the multiplicative split of the deformation gradient into growth and elastic contributions. The mechanical and biological response during tissue adaptation is characterized by inherent variability. Accounting for this uncertainty is critical to better understand tissue mechanobiology, and, moreover, it is of practical importance if we aim to develop predictive models for clinical use. However, the current gold standard in computational models of growth and remodeling remains the use of deterministic finite element (FE) simulations. Here we focus on tissue expansion, a popular technique in which skin is stretched by a balloon-like device inducing its growth. We construct FE models of tissue expansion with various levels of detail, and show that a sufficiently broad set of FE simulations from these models can be used to train an accurate and efficient multi-fidelity Gaussian process (GP) surrogate. The approach is not limited to simulation data, rather, it can fuse different kinds of data, including from experiments. The main appeal of the framework relies on the common experience that highly detailed models (or experiments) are more accurate but also more costly, while simpler models (or experiments) can be easily evaluated but are bound to have some error. In these situations, doing uncertainty analysis tasks with the high fidelity models alone is not feasible and, conversely, relying solely on low fidelity approximations is also undesirable. We show that a multi-fidelity GP outperforms the high fidelity GP and low fidelity GP when tested against the most detailed FE model. In turn, having trained the multi-fidelity GP model, we showcase the propagation of uncertainty from the mechanical and biological response parameters to the spatio-temporal growth outcomes. We expect that the methods and applications in this paper will enable future research in parameter calibration under uncertainty and uncertainty propagation in real clinical scenarios involving tissue growth and remodeling.

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

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