Fluid-like Tissues Research Articles

Cell jamming regulates epithelial chiral morphogenesis

Internal organs such as the heart demonstrate apparent left–right (LR) asymmetric morphology and positioning. Cellular chirality and associated LR biased mechanical behavior such as cell migration have been attributed to LR symmetry breaking during embryonic development. Mathematical models have shown that chiral directional migration can be driven by cellular intrinsic torque. Tissue jamming state (i.e., solid-like vs fluid-like state) strongly regulates collective migratory behavior, but how it might affect chiral morphogenesis is still unknown. Here, we develop a cell vertex model to study the role of tissue rigidity or jamming state on chiral morphogenesis of the cells on a patterned ring-shaped tissue, simulating a previously reported experimental setup for measuring cell chirality. We simulate chirality as torsional forces acting on cell vertices. As expected, the cells undergo bidirectional migration at the opposing (inner and outer) boundaries of the ring-shaped tissue. We discover that more fluid-like tissues (unjammed) demonstrate a stronger chiral cell alignment and elongation than more solid-like (jammed) tissues and maintain a bigger difference in migration velocity between opposing tissue boundaries. Finally, we find that fluid-like tissues undergo more cell-neighbor exchange events. This study reveals that chiral torque is sufficient to achieve a biased cellular alignment as seen in vitro. It further sheds light on the mechanical regulation of chiral morphogenesis of tissues and reveals a role of cell density-independent tissue rigidity in this process.

Shear-Driven Solidification and Nonlinear Elasticity in Epithelial Tissues.

Biological processes, from morphogenesis to tumor invasion, spontaneously generate shear stresses inside living tissue. The mechanisms that govern the transmission of mechanical forces in epithelia and the collective response of the tissue to bulk shear deformations remain, however, poorly understood. Using a minimal cell-based computational model, we investigate the constitutive relation of confluent tissues under simple shear deformation. We show that an initially undeformed fluidlike tissue acquires finite rigidity above a critical applied strain. This is akin to the shear-driven rigidity observed in other soft matter systems. Interestingly, shear-driven rigidity can be understood by a critical scaling analysis in the vicinity of the second order critical point that governs the liquid-solid transition of the undeformed system. We further show that a solidlike tissue responds linearly only to small strains and but then switches to a nonlinear response at larger stains, with substantial stiffening. Finally, we propose a mean-field formulation for cells under shear that offers a simple physical explanation of shear-driven rigidity and nonlinear response in a tissue.

Effect of cellular rearrangement time delays on the rheology of vertex models for confluent tissues.

Large-scale tissue deformation during biological processes such as morphogenesis requires cellular rearrangements. The simplest rearrangement in confluent cellular monolayers involves neighbor exchanges among four cells, called a T1 transition, in analogy to foams. But unlike foams, cells must execute a sequence of molecular processes, such as endocytosis of adhesion molecules, to complete a T1 transition. Such processes could take a long time compared to other timescales in the tissue. In this work, we incorporate this idea by augmenting vertex models to require a fixed, finite time for T1 transitions, which we call the "T1 delay time". We study how variations in T1 delay time affect tissue mechanics, by quantifying the relaxation time of tissues in the presence of T1 delays and comparing that to the cell-shape based timescale that characterizes fluidity in the absence of any T1 delays. We show that the molecular-scale T1 delay timescale dominates over the cell shape-scale collective response timescale when the T1 delay time is the larger of the two. We extend this analysis to tissues that become anisotropic under convergent extension, finding similar results. Moreover, we find that increasing the T1 delay time increases the percentage of higher-fold coordinated vertices and rosettes, and decreases the overall number of successful T1s, contributing to a more elastic-like-and less fluid-like-tissue response. Our work suggests that molecular mechanisms that act as a brake on T1 transitions could stiffen global tissue mechanics and enhance rosette formation during morphogenesis.

Anisotropy links cell shapes to tissue flow during convergent extension

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending Drosophila germband epithelium, which displays planar-polarized myosin II and experiences anisotropic forces from neighboring tissues. We show that, in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues, two experimentally accessible metrics of cell patterns-the cell shape index and a cell alignment index-are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in the Drosophila germband predict the onset of rapid cell rearrangement in both wild-type and snail twist mutant embryos, where our theoretical prediction is further improved when we also account for cell packing disorder. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue-shape changes during rapid developmental events.

A fluid-to-solid jamming transition underlies vertebrate body axis elongation.

Just as in clay molding or glass blowing, sculpting biological structures requires the constituent material to locally flow like a fluid while maintaining overall mechanical integrity like a solid. Disordered soft materials, such as foams, emulsions and colloidal suspensions, switch from fluid-like to solid-like behaviors at a jamming transition1–4. Similarly, cell collectives have been shown to display glassy dynamics in 2D and 3D5,6 and jamming in cultured epithelial monolayers7,8, behaviors recently predicted theoretically9–11 and proposed to influence asthma pathobiology8 and tumor progression12. However, it is unknown if these seemingly universal behaviors occur in vivo and, specifically, if they play any functional role during embryonic morphogenesis. By combining direct in vivo measurements of tissue mechanics with analysis of cellular dynamics, we show that during vertebrate body axis elongation, posterior tissues undergo a jamming transition from a fluid-like behavior at the extending end, the mesodermal progenitor zone (MPZ), to a solid-like behavior in the presomitic mesoderm (PSM). We uncover an anteroposterior, N-cadherin-dependent gradient in yield stress that provides increasing mechanical integrity to the PSM, consistent with the tissue transiting from a wetter to a dryer foam-like architecture. Our results show that cell-scale stresses fluctuate rapidly (~1 min), enabling cell rearrangements and effectively ‘melting’ the tissue at the growing end. Persistent (>0.5 h) stresses at supracellular scales, rather than cell-scale stresses, guide morphogenetic flows in fluid-like tissue regions. Unidirectional axis extension is sustained by the reported PSM rigidification, which mechanically supports posterior, fluid-like tissues during remodeling prior to their maturation. The spatiotemporal control of fluid-like and solid-like tissue states may represent a generic physical mechanism of embryonic morphogenesis.

How do Single-Cell Properties Influence the Collective Mechanical Behavior of Confluent Tissues?

Biological tissues involved in important processes such as embryonic development, lung function, wound healing, and cancer progression have recently been shown, via a systematic analysis of tissue mechanics and cell displacement statistics, to be close to a disordered liquid-to-solid or “jamming” transition. We expect these jamming transitions to be very important for biological function. For example, due to collective effects, cell migration is greatly reduced in solid-like tissues and enhanced in fluid-like tissues. Therefore, we would like to know how cells might regulate properties such as expression of cell-cell adhesion molecules and myosin activity in order to change the macroscopic properties of the tissue as a whole. I will discuss a new theoretical framework that predicts how the jamming transition is governed by single-cell mechanics and persistent cell motility. I will discuss how our a priori theoretical predictions with no fit parameters are precisely realized in cell cultures from human patients with asthma, and discuss how these ideas might also be applied in heterogeneous cell populations to understand processes in embryonic development and cancer progression.

Asymptotic behavior of solutions of a free boundary problem modeling the growth of tumors with fluid-like tissue under the action of inhibitors

Asymptotic behavior of solutions of a free boundary problem modeling the growth of tumors with fluid-like tissue under the action of inhibitors

Dissipative particle dynamics simulations for biological tissues: rheology and competition

In this work, we model biological tissues using a simple, mechanistic simulation based on dissipative particle dynamics. We investigate the continuum behavior of the simulated tissue and determine its dependence on the properties of the individual cell. Cells in our simulation adhere to each other, expand in volume, divide after reaching a specific size checkpoint and undergo apoptosis at a constant rate, leading to a steady-state homeostatic pressure in the tissue. We measure the dependence of the homeostatic state on the microscopic parameters of our model and show that homeostatic pressure, rather than the unconfined rate of cell division, determines the outcome of tissue competitions. Simulated cell aggregates are cohesive and round up due to the effect of tissue surface tension, which we measure for different tissues. Furthermore, mixtures of different cells unmix according to their adhesive properties. Using a variety of shear and creep simulations, we study tissue rheology by measuring yield stresses, shear viscosities, complex viscosities as well as the loss tangents as a function of model parameters. We find that cell division and apoptosis lead to a vanishing yield stress and fluid-like tissues. The effects of different adhesion strengths and levels of noise on the rheology of the tissue are also measured. In addition, we find that the level of cell division and apoptosis drives the diffusion of cells in the tissue. Finally, we present a method for measuring the compressibility of the tissue and its response to external stress via cell division and apoptosis.

Regularity of solutions to a free boundary problem modeling tumor growth by Stokes equation

In this paper we investigate regularity of solutions to a free boundary problem modeling tumor growth in fluid-like tissues. The model equations include a quasi-stationary diffusion equation for the nutrient concentration, and a Stokes equation with a source representing the proliferation density of the tumor cells, subject to a boundary condition with stress tensor effected by surface tension. This problem is a fully nonlinear problem involving nonlocal terms. Based on the employment of the functional analytic method and the theory of maximal regularity, we prove that the free boundary of this problem is real analytic in temporal and spatial variables for initial data of less regularity.

Asymptotic Stability of Stationary Solutions of a Free Boundary Problem Modeling the Growth of Tumors with Fluid Tissues

This paper aims at proving asymptotic stability of the radial stationary solution of a free boundary problem modeling the growth of nonnecrotic tumors with fluid-like tissues. In a previous paper we considered the case where the nutrient concentration $\sigma$ satisfies the stationary diffusion equation $\Delta\sigma=f(\sigma)$ and proved that there exists a threshold value $\gamma_*>0$ for the surface tension coefficient $\gamma$, such that the radial stationary solution is asymptotically stable in case $\gamma>\gamma_*$, while unstable in case $\gamma<\gamma_*$. In this paper we extend this result to the case where $\sigma$ satisfies the nonstationary diffusion equation $\varepsilon\partial_t\sigma=\Delta\sigma-f(\sigma)$. We prove that for the same threshold value $\gamma_*$ as above, for every $\gamma>\gamma_*$, there is a corresponding constant $\varepsilon_0(\gamma)>0$ such that for any $0<\varepsilon<\varepsilon_0(\gamma)$, the radial stationary solution is asymptotically stable with respect to small enough nonradial perturbations, while for $0<\gamma<\gamma_*$ and $\varepsilon$ sufficiently small, it is unstable under nonradial perturbations.

Asymptotic behavior of solutions of a free boundary problem modelling the growth of tumors with Stokes equations

We study a free boundary problem modelling the growth of non-necrotic tumors with fluid-like tissues. The fluid velocity satisfies Stokes equations with a source determined by the proliferation rate of tumor cells which depends on the concentration of nutrients, subject to a boundary condition with stress tensor effected by surface tension. It is easy to prove that this problem has a unique radially symmetric stationary solution. By using a functional approach, we prove that there exists a threshold value γ* > 0 for the surface tension coefficient $\gamma$, such that in the case γ > γ* this radially symmetric stationary solution is asymptotically stable under small non-radial perturbations, whereas in the opposite case it is unstable.

MATHEMATICAL ANALYSIS AND CHALLENGES ARISING FROM MODELS OF TUMOR GROWTH

In the last four decades, various cancer models have been developed in which the evolution of the densities of cells (abnormal, normal, or dead) and the concentrations of biochemical species are described in terms of differential equations. In this paper, we deal with tumor models in which the tumor occupies a well-defined region in space; the boundary of this region is held together by the forces of cell-to-cell adhesion. We shall refer to such tumors as "solid" tumors, although they may sometimes consist of fluid-like tissue, such as in the case of brain tumors (e.g. gliomas) and breast tumors. The most common class of solid tumors is carcinoma: a cancer originating from epithelial cells, that is, from the closely packed cells which align the internal cavities of the body. Models of solid tumors must take spatial effects into account, and are therefore described in terms of partial differential equations (PDEs). They also need to take into account the fact that the tumor region is changing in time; in fact, the tumor region, say Ω(t), and its boundary Γ(t), are unknown in advance. Thus one needs to determine both the unknown "free boundary" Γ(t) together with the solution of the PDEs in Ω(t). These types of problems are called free boundary problems. The models described in this paper are free boundary problems, and our primary interest is the spatial/geometric features of the free boundary. Some of the basic questions we shall address are: What is the shape of the free boundary? How does the free boundary behave as t → ∞? Does the tumor volume increase or shrink as t → ∞? Under what conditions does the tumor eventually become dormant? Finally, we shall explore the dependence of the free boundary on some biological parameters, and this will give rise to interesting bifurcation phenomena. The structure of the paper is as follows. In Secs. 1 and 2 we consider models in which all the cells are of one type, they are all proliferating cells. The tissue is modeled either as a porous medium (in Sec. 1) or as a fluid medium (in Sec. 2). The models are extended in Secs. 3 and 4 to include three types of cells: proliferating, quiescent, and dead. Finally, in Sec. 5 we outline a general multiphase model that includes gene mutations.

Bifurcation from stability to instability for a free boundary problem modeling tumor growth by Stokes equation

We consider a free boundary problem modeling tumor growth in fluid-like tissue. The model equations include a diffusion equation for the nutrient concentration, and the Stokes equation with a source which represents the proliferation of tumor cells. The proliferation rate μ and the cell-to-cell adhesiveness γ which keeps the tumor intact are two parameters which characterize the “aggressiveness” of the tumor. For any positive radius R there exists a unique radially symmetric stationary solution with radius r = R . For a sequence μ / γ = M n ( R ) there exist symmetry-breaking bifurcation branches of solutions with free boundary r = R + ε Y n , 0 ( θ ) + O ( ε 2 ) ( n even ⩾2) for small | ε | , where Y n , 0 is the spherical harmonic of mode ( n , 0 ) . Furthermore, the smallest M n ( R ) , say M n ∗ ( R ) , is such that n ∗ = n ∗ ( R ) → ∞ as R → ∞ . In this paper we prove that the radially symmetric stationary solution with R = R S is linearly stable if μ / γ < N ∗ ( R S , γ ) and linearly unstable if μ / γ > N ∗ ( R S , γ ) , where N ∗ ( R S , γ ) ⩽ M n ∗ ( R S ) , and we prove that strict inequality holds if γ is small or if γ is large. The biological implications of these results are discussed at the end of the paper.