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

Abstract

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.

Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix

“…Langevin equations assume that cell motion occurs in the overdamped regime which is a valid assumption for cellular modeling in most biological systems [54][55][56][57]. Each Langevin equation includes a constant damping term.…”

“…To solve Eqs 1-3, the explicit Euler method was applied, and model simulations were carried out on a cluster of graphical processing units (GPUs) to accelerate the computation. (For more detailed information about discretization and GPU implementation, please see [57]. )…”

“…Cell-cell adhesion and cell-ECM adhesion model parameters were calibrated using experimentally obtained values of adhesion for epithelial cells [57] since it was reported that the level of cell-cell adhesion for epithelial cells is in the same range as the cell-ECM adhesion [59]. The size and number of cells in the model were calibrated using experimentally observed shapes of epithelial cells ( Table 2).…”

Cell–substrate mechanics guide collective cell migration through intercellular adhesion: a dynamic finite element cellular model

“…Recently, computational models have become increasingly useful to complement experimental observations towards understanding the mechanisms of collective cell migration. A number of computational cell models have been developed to study the mechanical interactions between cells or between cell and ECM (Albert and Schwarz, 2016;Basan et al, 2013;Checa et al, 2015;Drasdo and Hoehme, 2012;Hoehme and Drasdo, 2010;Hutson et al, 2009;Kabla, 2012;Kachalo et al, 2015;Kim et al, 2018Kim et al, , 2015Lee and Wolgemuth, 2011;Lee et al, 2017;Marée et al, 2007;Merchant et al, 2018;Nagai and Honda, 2009;Nematbakhsh et al, 2017;Sandersius et al, 2011;Van Liedekerke et al, 2019;Vermolen and Gefen, 2015;Vitorino et al, 2011;Zhao et al, 2013). However, these models have limitations.…”

“…Finite element models have also been developed, but they only allowed limited changes in cell shape and limited flexibility in cell movement (Hutson et al, 2009;Vermolen and Gefen, 2015;Zhao et al, 2013). Other models mimic the cellular mechanics using arbitrarily imposed Morse potential which is unrealistic at cellular level (Nematbakhsh et al, 2017;Sandersius et al, 2011). In many cases, details of the intercellular adhesions are not considered (Basan et al, 2013;Checa et al, 2015;Drasdo and Hoehme, 2012;Hoehme and Drasdo, 2010;Hutson et al, 2009;Kabla, 2012;Kim et al, 2018Kim et al, , 2015Lee and Wolgemuth, 2011;Lee et al, 2017;Merchant et al, 2018;Nagai and Honda, 2009;Van Liedekerke et al, 2019;Vermolen and Gefen, 2015;Vitorino et al, 2011).…”