Cell cycle–dependent active stress drives epithelia remodeling

Abstract

Epithelia have distinct cellular architectures which are established in development, reestablished after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here, we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here, we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop an extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly, but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics are arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions, the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics.

Tight Junction ZO Proteins Maintain Tissue Fluidity, Ensuring Efficient Collective Cell Migration

“…[61] The observation that MDCK cells at low densities show such a high, and at higher densities, a significantly lower power-law exponent is shared by recent experimental evidence. [62,63] This general effect of cell density on collective migration dynamics is also in line with physical particle-based models of tissue dynamics. [39] These models predict cell density to be the main determinant parameter for collective motility with motion arrest at high densities.…”

“…showed in simulations and experiments that absolute changes of the cell shape can vary greatly and could thus be inconclusive, depending on the experimental situation. [ 62 ] Importantly, Saraswathibhatla and Notbohm found a correlation between cell density, shape, and motility. [ 63 ] While we only observe small changes in cell shape, we do observe a similar impact on cell density.…”

Jamming in Embryogenesis and Cancer Progression

“…Their neighbors cage cells within the sheet while the whole sheet collectively moves [58,77]. Conversely, tissues could be in a non-rigid, low tension, unjammed state with only minimal or vacant cell motion insufficient for active neighbor exchange [78]. The relation between rigidity and jamming is of particular interest in cancer development.…”

Cell cycle dynamics controls fluidity of the developing mouse neuroepithelium

“…The regulation of tissue fluidity has previously been linked to changes in cell density, mechanical properties, such as cell adhesion, cortical tension, contractility, as well as signaling pathways such as Wnt/PCP and Ffg (2,3,5,6,37,(39)(40)(41). By contrast, the role of cell divisions, apart from a few experimental examples (3,9,10) and theoretical predictions (8,42), has been largely underappreciated. Given that cell cycle lengthening is observed in multiple developing tissues (43)(44)(45), our findings raise the possibility that these tissues also undergo effective cell-cycle driven increase in rigidity over time.…”

“…In most cases, these changes have been proposed to result from solid-fluid transitions driven by alterations in cell density, internal myosin and/or cadherin-mediated adhesion forces at cell junctions, or external mechanical forces (2)(3)(4)(5)(6)(7). Cell rearrangements have also been shown in theory and in some experimental situations to depend on active stresses within tissues, such as the ones generated by cell division (8)(9)(10)(11). Yet, in many cases, the dynamics of cell rearrangements and the factors that control them are poorly understood.…”