Mechanical control of cell proliferation patterns in growing epithelial monolayers.

Cell proliferation plays a crucial role in regulating tissue homeostasis and development. However, our understanding of how cell proliferation is controlled in densely packed tissues is limited. Here we develop a computational framework to predict the patterns of cell proliferation in growing epithelial tissues, connecting single-cell behaviors and cell-cell interactions to tissue-level growth. Our model incorporates probabilistic rules governing cell growth, division, and elimination, also taking into account their feedback with tissue mechanics. In particular, cell growth is suppressed and apoptosis is enhanced in regions of high cell density. With these rules and model parameters calibrated using experimental data for epithelial monolayers, we predict how tissue confinement influences cell size and proliferation dynamics and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. In this model, mechanical feedback between tissue confinement and cell growth leads to enhanced cell proliferation at tissue boundaries, whereas cell growth in the bulk is arrested, recapitulating experimental observations in epithelial tissues. By tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. We show that the cell size threshold at G1/S transition governs the homeostatic cell density and tissue turnover rate, whereas the mechanical state of the tissue governs the dynamics of tissue growth. In particular, we find that the cellular parameters affecting tissue pressure play a significant role in determining the overall growth rate. Our computational study thus underscores the impact of cell mechanical properties on the spatiotemporal patterns of cell proliferation in growing epithelial tissues.

Continuum description of confluent tissues with spatial heterogeneous activity.

A continuum description is built to characterize the stationary and transient deformations of confluent tissues subject to heterogeneous activities. By defining a coarse-grained texture matrix field to represent the shape and size of cells, we derive the coarse-grained stress tensor for the vertex model. Activity in the tissue takes the form of inhomogeneous apical contractions, which can be modeled as reductions of the vertex model reference areas or perimeters representing activity in the medial and perimeter regions of the cells, respectively. For medial activity, the extra stress is just an isotropic pressure, while for perimeter activity, it also has a deviatoric component, which is aligned with the texture matrix. The predictions of the continuum description are compared with the average spatiotemporal deformations obtained in simulations of the vertex model subject to localized apical contractions, showing an excellent agreement, even if the active patch is as small as one cell. The fluctuations around the average are more prominent when the activity is in the medial region due to the lack of negative active shape feedback, which, coupled with the confluent property, increases cellular shape and size variations.

Mechanical control of cell proliferation patterns in growing tissues.

Cell proliferation plays a crucial role in regulating tissue homeostasis and development. However, our understanding of how cell proliferation is controlled in densely packed tissues is limited. Here we develop a computational framework to predict the patterns of cell proliferation in growing tissues, connecting single-cell behaviors and cell-cell interactions to tissue-level growth. Our model incorporates probabilistic rules governing cell growth, division, and elimination, while also taking into account their feedback with tissue mechanics. In particular, cell growth is suppressed and apoptosis is enhanced in regions of high cell density. With these rules and model parameters calibrated using experimental data, we predict how tissue confinement influences cell size and proliferation dynamics, and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. Our findings indicate that mechanical feedback between tissue confinement and cell growth leads to enhanced cell proliferation at tissue boundaries, whereas cell growth in the bulk is arrested. By tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. Furthermore, mechanical state of the tissue governs the dynamics of tissue growth, with cellular parameters affecting tissue pressure playing a significant role in determining the overall growth rate. Our computational study thus underscores the impact of cell mechanical properties on the spatiotemporal patterns of cell proliferation in growing tissues.

Geometrical characterization of active contraction pulses in epithelial cells using the two-dimensional vertex model.

Several models have been proposed to describe the dynamics of epithelial tissues undergoing morphogenetic changes driven by apical constriction pulses, which differ in where the constriction is applied, either at the perimeter or in the medial regions. To help discriminate between these models, we analyse the impact of where constriction is applied on the final geometry of the active contracted cell, using the two-dimensional vertex model. We find that medial activity, characterized by a reduction in the reference area, generates anisotropic cell shapes, whereas isotropic cell shapes are produced when the reference perimeter is reduced. When plasticity is included, sufficiently slow processes of medial contractile activity, compared with the characteristic times of elasticity and plasticity, cells can achieve less elongated shapes. Similarly, for perimeter activity, the highest level of contraction is achieved. Finally, we apply the model to describe the apical contractile pulses observed within the epithelial enveloping cell layer during the pre-epiboly of the annual killifish Austrolebias nigripinnis. The analysis of the cell shape changes allowed a global fit of all parameters of the vertex model, with the pulses being quantitatively captured using perimeter activity and area plasticity.

Vertex model instabilities for tissues subject to cellular activity or applied stresses.

The vertex model is widely used to describe the dynamics of epithelial tissues, because of its simplicity and versatility and the direct inclusion of biophysical parameters. Here, it is shown that quite generally, when cells modify their equilibrium perimeter due to their activity, or the tissue is subject to external stresses, the tissue becomes unstable with deformations that couple pure shear or deviatoric modes, with rotation and expansion modes. For short times, these instabilities deform cells, increasing their ellipticity, while at longer times cells become nonconvex, indicating that the vertex model ceases to be a valid description for tissues under these conditions. The agreement between the analytic calculations performed for a regular hexagonal tissue and the simulations of disordered tissues is excellent due to the homogenization of the tissue at long wavelengths.