Multi-scale computational study of the mechanical regulation of cell mitotic rounding in epithelia

• Published in: PLoS computational biology Vol. 13; no. 5; p. e1005533
• Main Authors: Nematbakhsh, Ali, Sun, Wenzhao, Brodskiy, Pavel A, Amiri, Aboutaleb, Narciso, Cody, Xu, Zhiliang, Zartman, Jeremiah J, Alber, Mark
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-05-2017; Public Library of Science (PLoS)
• Subjects: Aneuploidy; Animals; Biology and Life Sciences; Calibration; Cancer; Cell adhesion; Cell adhesion & migration; Cell cycle; Cell division; Cell Line; Cell Shape - physiology; Chromosomes; Circularity; Colleges & universities; Computational Biology; Computational mathematics; Computer applications; Computer simulation; Control; Cortex; Cytoplasm; Drosophila; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - physiology; Experimental data; Humans; Insects; Mathematical models; Mathematics; Mechanical properties; Medicine and Health Sciences; Microscopy; Mitosis; Mitosis - physiology; Models, Biological; Morphogenesis; Multiscale analysis; Observations; Osmosis; Osmotic pressure; Physical Sciences; Physiological aspects; Physiology; Prediction models; Regression analysis; Representations; Research and Analysis Methods; Robustness; Rounding; Roundness; Scale (ratio); Scholarships & fellowships; Simulation; Stiffness; Tissues; Tumors; Indiana; United States > US; California
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1005533

Mitotic rounding during cell division is critical for preventing daughter cells from inheriting an abnormal number of chromosomes, a condition that occurs frequently in cancer cells. Cells must significantly expand their apical area and transition from a polygonal to circular apical shape to achieve robust mitotic rounding in epithelial tissues, which is where most cancers initiate. However, how cells mechanically regulate robust mitotic rounding within packed tissues is unknown. Here, we analyze mitotic rounding using a newly developed multi-scale subcellular element computational model that is calibrated using experimental data. Novel biologically relevant features of the model include separate representations of the sub-cellular components including the apical membrane and cytoplasm of the cell at the tissue scale level as well as detailed description of cell properties during mitotic rounding. Regression analysis of predictive model simulation results reveals the relative contributions of osmotic pressure, cell-cell adhesion and cortical stiffness to mitotic rounding. Mitotic area expansion is largely driven by regulation of cytoplasmic pressure. Surprisingly, mitotic shape roundness within physiological ranges is most sensitive to variation in cell-cell adhesivity and stiffness. An understanding of how perturbed mechanical properties impact mitotic rounding has important potential implications on, amongst others, how tumors progressively become more genetically unstable due to increased chromosomal aneuploidy and more aggressive.