A unified rheological model for cells and cellularised materials.

The mechanical response of single cells and tissues exhibits a broad distribution of time-scales that often gives rise to a distinctive power-law rheology. Such complex behaviour cannot be easily captured by traditional rheological approaches, making material characterisation and predictive modelling very challenging. Here, we present a novel model combining conventional viscoelastic elements with fractional calculus that successfully captures the macroscopic relaxation response of epithelial monolayers. The parameters extracted from the fitting of the relaxation modulus allow prediction of the response of the same material to slow stretch and creep, indicating that the model captured intrinsic material properties. Two characteristic times, derived from the model parameters, delimit different regimes in the materials response. We compared the response of tissues with the behaviour of single cells as well as intra and extra-cellular components, and linked the power-law behaviour of the epithelium to the dynamics of the cell cortex. Such a unified model for the mechanical response of biological materials provides a novel and robust mathematical approach to consistently analyse experimental data and uncover similarities and differences in reported behaviour across experimental methods and research groups. It also sets the foundations for more accurate computational models of tissue mechanics

Strain-induced alignment in collagen gels

Collagen is the most abundant extracellular-network-forming protein in animal biology and is important in both natural and artificial tissues, where it serves as a material of great mechanical versatility. This versatility arises from its almost unique ability to remodel under applied loads into anisotropic and inhomogeneous structures. To explore the origins of this property, we develop a set of analysis tools and a novel experimental setup that probes the mechanical response of fibrous networks in a geometry that mimics a typical deformation profile imposed by cells in vivo. We observe strong fiber alignment and densification as a function of applied strain for both uncrosslinked and crosslinked collagenous networks. This alignment is found to be irreversibly imprinted in uncrosslinked collagen networks, suggesting a simple mechanism for tissue organization at the microscale. However, crosslinked networks display similar fiber alignment and the same geometrical properties as uncrosslinked gels, but with full reversibility. Plasticity is therefore not required to align fibers. On the contrary, our data show that this effect is part of the fundamental non-linear properties of fibrous biological networks.Comment: 12 pages, 7 figures. 1 supporting material PDF with 2 figure

Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination.

Heterogeneity within tumour cell populations is commonly observed in most cancers. However, its impact on metastatic dissemination, one of the primary determinants of the disease prognosis, remains poorly understood. Working with a simplified numerical model of tumour spheroids, we investigated the impact of mechanical heterogeneity on the onset of tumour invasion into surrounding tissues. Our work establishes a positive link between tumour heterogeneity and metastatic dissemination, and recapitulates a number of invasion patterns identified in vivo, such as multicellular finger-like protrusions. Two complementary mechanisms are at play in heterogeneous tumours. A small proportion of stronger cells are able to initiate and lead the escape of cells, while collective effects in the bulk of the tumour provide the coordination required to sustain the invasive process through multicellular streaming. This suggests that the multicellular dynamics observed during metastasis is a generic feature of mechanically heterogeneous cell populations and might rely on a limited and generic set of attributes

Hydraulic fracturing in cells and tissues: fracking meets cell biology

The animal body is fundamentally made of water. A small fraction of this water is freely flowing in blood and lymph, but most of it is trapped in hydrogels such as the extracellular matrix (ECM), the cytoskeleton, and chromatin. Besides providing a medium for biological molecules to diffuse, water trapped in hydrogels plays a fundamental mechanical role. This role is well captured by the theory of poroelasticity, which explains how any deformation applied to a hydrogel causes pressure gradients and water flows, much like compressing a sponge squeezes water out of it. Here we review recent evidence that poroelastic pressures and flows can fracture essential biological barriers such as the nuclear envelope, the cellular cortex, and epithelial layers. This type of fracture is known in engineering literature as hydraulic fracturing or "fracking"Peer ReviewedPostprint (author's final draft

Reaction–Diffusion Finite Element Model of Lateral Line Primordium Migration to Explore Cell Leadership

Collective cell migration plays a fundamental role in many biological phenomena such as immune response, embryogenesis and tumorigenesis. In the present work, we propose a reaction–diffusion finite element model of the lateral line primordium migration in zebrafish. The population is modelled as a continuum with embedded discrete motile cells, which are assumed to be viscoelastic and able to undergo large deformations. The Wnt/ß-catenin–FGF and cxcr4b–cxcr7b signalling pathways inside the cohort regulating the migration are described through coupled reaction–diffusion equations. The coupling between mechanics and the molecular scenario occurs in two ways. Firstly, the intensity of the protrusion–contraction movement of the cells depends on the cxcr4b concentration. Secondly, the intra-synchronization between the active deformations and the adhesion forces inside each cell is triggered by the cxcr4b–cxcr7b polarity. This influences the inter-synchronization between the cells and results in two main modes of migration: uncoordinated and coordinated. The main objectives of the work were (i) to validate our assumptions with respect to the experimental observations and (ii) to decipher the mechanical conditions leading to efficient migration of the primordium. To achieve the second goal, we will specifically focus on the role of the leader cells and their position inside the population

Toward high-content/high-throughput imaging and analysis of embryonic morphogenesis

In vivo study of embryonic morphogenesis tremendously benefits from recent advances in live microscopy and computational analyses. Quantitative and automated investigation of morphogenetic processes opens the field to high-content and high-throughput strategies. Following experimental workflow currently developed in cell biology, we identify the key challenges for applying such strategies in developmental biology. We review the recent progress in embryo preparation and manipulation, live imaging, data registration, image segmentation, feature computation, and data mining dedicated to the study of embryonic morphogenesis. We discuss a selection of pioneering studies that tackled the current methodological bottlenecks and illustrated the investigation of morphogenetic processes in vivo using quantitative and automated imaging and analysis of hundreds or thousands of cells simultaneously, paving the way for high-content/high-throughput strategies and systems analysis of embryonic morphogenesis

Tractions and stress fibers control cell shape and rearrangements in collective cell migration

Key to collective cell migration is the ability of cells to rearrange their position with respect to their neighbors. Recent theory and experiments demonstrated that cellular rearrangements are facilitated by cell shape, with cells having more elongated shapes and greater perimeters more easily sliding past their neighbors within the cell layer. Though it is thought that cell perimeter is controlled primarily by cortical tension and adhesion at each cell's periphery, experimental testing of this hypothesis has produced conflicting results. Here we studied collective cell migration in an epithelial monolayer by measuring forces, cell perimeters, and motion, and found all three to decrease with either increased cell density or inhibition of cell contraction. In contrast to previous understanding, the data suggest that cell shape and rearrangements are controlled not by cortical tension or adhesion at the cell periphery but rather by the stress fibers that produce tractions at the cell-substrate interface. This finding is confirmed by an experiment showing that increasing tractions reverses the effect of density on cell shape and rearrangements. Our study therefore reduces the focus on the cell periphery by establishing cell-substrate traction as a major physical factor controlling cell shape and motion in collective cell migration.Comment: 39 pages, 6 figure

Tensile Forces and Mechanotransduction at Cell-Cell Junctions

Cell-cell junctions are specializations of the plasma membrane responsible for physically integrating cells into tissues. We are now beginning to appreciate the diverse impacts that mechanical forces exert upon the integrity and function of these junctions. Currently, this is best understood for cadherin-based adherens junctions in epithelia and endothelia, where cell-cell adhesion couples the contractile cytoskeletons of cells together to generate tissue-scale tension. Junctional tension participates in morphogenesis and tissue homeostasis. Changes in tension can also be detected by mechanotransduction pathways that allow cells to communicate with each other. In this review, we discuss progress in characterising the forces present at junctions in physiological conditions; the cellular mechanisms that generate intrinsic tension and detect changes in tension; and, finally, we consider how tissue integrity is maintained in the face of junctional stresses

Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors.

During embryogenesis tissue layers undergo morphogenetic flow rearranging and folding into specific shapes. While developmental biology has identified key genes and local cellular processes, global coordination of tissue remodeling at the organ scale remains unclear. Here, we combine in toto light-sheet microscopy of the Drosophila embryo with quantitative analysis and physical modeling to relate cellular flow with the patterns of force generation during the gastrulation process. We find that the complex spatio-temporal flow pattern can be predicted from the measured meso-scale myosin density and anisotropy using a simple, effective viscous model of the tissue, achieving close to 90% accuracy with one time dependent and two constant parameters. Our analysis uncovers the importance of a) spatial modulation of myosin distribution on the scale of the embryo and b) the non-locality of its effect due to mechanical interaction of cells, demonstrating the need for the global perspective in the study of morphogenetic flow