Martine Ben Amar

Anisotropic growth shapes intestinal tissues during embryogenesis

Embryogenesis offers a real laboratory for pattern formation, buckling, and postbuckling induced by growth of soft tissues. Each part of our body is structured in multiple adjacent layers: the skin, the brain, and the interior of organs. Each layer has a complex biological composition presenting different elasticity. Generated during fetal life, these layers will experience growth and remodeling in the early postfertilization stages. Here, we focus on a herringbone pattern occurring in fetal intestinal tissues. Common to many mammalians, this instability is a precursor of the villi, finger-like projections into the lumen. For avians (chicks’ and turkeys’ embryos), it has been shown that, a few days after fertilization, the mucosal epithelium of the duodenum is smooth, and then folds emerge, which present 2 d later a pronounced zigzag instability. Many debates and biological studies are devoted to this specific morphology, which regulates the cell renewal in the intestine. After reviewing experimental results about duodenum morphogenesis, we show that a model based on simplified hypothesis for the growth of the mesenchyme can explain buckling and postbuckling instabilities. Being completely analytical, it is based on biaxial compressive stresses due to differential growth between layers and it predicts quantitatively the morphological changes. The growth anisotropy increasing with time, the competition between folds and zigzags, is proved to occur as a secondary instability. The model is compared with available experimental data on chick’s duodenum and can be applied to other intestinal tissues, the zigzag being a common and spectacular microstructural pattern of intestine embryogenesis.

Dynamics of singularities in a constrained elastic plate

Large deformations of thin elastic plates usually lead to the formation of singular structures which are either linear (ridges) or pointlike (developable cones). These structures are thought to be generic for crumpled plates, although they have been investigated quantitatively only in simplified geometries. Previous studies have also shown that a large number of singularities are generated by successive instabilities. Here we study, experimentally and numerically, a generic situation in which a plate is initially bent in one direction into a cylindrical arch, then deformed in the other direction by a load applied at its centre. This induces the generation of pairs of singularities; we study their position, their dynamics and the corresponding resistance of the plate to deformation. We solve numerically the equations describing large deformations of plates; developable cones are predicted, in quantitative agreement with the experiments. We use geometrical arguments to predict the observed patterns, assuming that the energy of the plate is given by the energy of the singularities.

Towards a unified approach in the modeling of fibrosis: A review with research perspectives

Pathological fibrosis is the result of a failure in the wound healing process. The comprehension and the related modeling of the different mechanisms that trigger fibrosis are a challenge of many researchers that work in the field of medicine and biology. The modern scientific analysis of a phenomenon generally consists of three major approaches: theoretical, experimental, and computational. Different theoretical tools coming from mathematics and physics have been proposed for the modeling of the physiological and pathological fibrosis. However a complete framework is missing and the development of a general theory is required. This review aims at finding a unified approach in the modeling of fibrosis diseases that takes into account the different phenomena occurring at each level: molecular, cellular and tissue. Specifically by means of a critical analysis of the different models that have been proposed in the mathematical, computational and physical biology, from molecular to tissue scales, a multiscale approach is proposed, an approach that has been strongly recommended by top level biologists in the past decades.

Morpho-elasticity of inflammatory fibrosis: the case of capsular contracture.

Inflammatory fibrosis is a wound-healing reaction of the immune system in mammals against aggression. After a signalling cascade, fibroblasts and potentially myofibroblasts make a stiff collagenous tissue inside the body that modifies the original healthy tissue. We focus here on the implant-induced fibrosis that aims to encapsulate the implant with a typical fibrous tissue called the capsule. Focusing on breast capsules, we aim to understand the mechanical properties of these tissues, to test the validity of fibre models that have been established in other contexts such as arteries. For this purpose, we perform force–extension experiments and show that mechanical constitutive laws of these tissues are especially difficult to derive, because models are sensitive to fibre orientation and dispersion, independently of the variation between individuals. In addition, fibre breakdown, and possibly remodelling, occur during the extension experiments. However, the high stiffness of the capsular tissue, compared with the healthy tissue, added to the fact that an inflammatory process has no reason to cease, is at the origin of large compressive stresses in vivo, which explains the pain and unaesthetic deformity. We evaluate the stresses responsible for the pain and the buckling instability, which have no reason to stop if the inflammation persists.

Patterns in biofilms: From contour undulations to fold focussing

Morphologies of soft materials in growth, swelling or drying have been extensively studied recently. Shape modifications occur as the size varies transforming ordinary spheres, cylinders and thin plates into more or less complex objects. Here we consider the genesis of biofilm patterns when a simple disc containing initially bacteria with moderate adhesion to a rigid substrate grows according to very simple rules. The initial circular geometry is lost during the growth expansion, contour undulations and buckling appear, ultimately a rather regular periodic focussing of folds repartition emerges. We theoretically predict these morphological instabilities as bifurcations of solutions in elasticity, characterized by typical driving parameters established here. The substrate plays a critical role limiting the geometry of the possible modes of instabilities and anisotropic growth, adhesion and toughness compete to eventually give rise to wrinkling, buckling or both. Additionally, due to the substrate, we show that the ordinary buckling modes, vertical deviation of thin films, are not observed in practice and a competitive pattern with self-focussing of folds can be found analytically. These patterns are reminiscent of the blisters of delamination in material sciences and explain recent observations of bacteria biofilms. The model presented here is purely analytical, is based on a neo-Hookean elastic energy, and can be extended without difficulties and applied to polymer materials.

Morphology of melanocytic lesions in situ

Melanoma is a solid tumour with its own specificity from the biological and morphological viewpoint. On one hand, numerous mutations are already known affecting different pathways. They usually concern proliferation rate, apoptosis, cell senescence and cell behaviour. On the other hand, several visual criteria at the tissue level are used by physicians in order to diagnose skin lesions. Nevertheless, the mechanisms between the changes from the mutations at the cell level to the morphology exhibited at the tissue level are still not fully understood. Using physical tools, we develop a simple model. We demonstrate analytically that it contains the necessary ingredients to understand several specificities of melanoma such as the presence of microstructures inside a skin lesion or the absence of a necrotic core. We also explain the importance of senescence for growth arrest in benign skin lesions. Thanks to numerical simulations, we successfully compare this model to biological data.

The interplay of stiffness and force anisotropies drives embryo elongation

The morphogenesis of tissues, like the deformation of an object, results from the interplay between their material properties and the mechanical forces exerted on them. The importance of mechanical forces in influencing cell behaviour is widely recognized, whereas the importance of tissue material properties, in particular stiffness, has received much less attention. Using Caenorhabditis elegans as a model, we examine how both aspects contribute to embryonic elongation. Measuring the opening shape of the epidermal actin cortex after laser nano-ablation, we assess the spatiotemporal changes of actomyosin-dependent force and stiffness along the antero-posterior and dorso-ventral axis. Experimental data and analytical modelling show that myosin-II-dependent force anisotropy within the lateral epidermis, and stiffness anisotropy within the fiber-reinforced dorso-ventral epidermis are critical in driving embryonic elongation. Together, our results establish a quantitative link between cortical tension, material properties and morphogenesis of an entire embryo. DOI: http://dx.doi.org/10.7554/eLife.23866.001

Theoretical analysis of growth or swelling wrinkles on constrained soft slabs

Growth or swelling of soft slabs attached to a rigid substrate generates large compressive stresses at their surfaces. When the stresses exceed a critical value, the smooth surface becomes unstable. For an in-plane isotropic material, a nonlinear three dimensional analysis is employed to ascertain the energy in the buckled state for different modes: stripes, squares and hexagons. When increasing the growth control parameter, we show that hexagonal patterns with a dimple at the center minimize the elastic energy and will be the dominant mode if the mode with minimal energy is the most likely to be observed. The growth of an anisotropic material reinforced by fibers is also considered. The results provide a way to understand surface wrinkling patterns induced by equi-biaxial growth or swelling of elastic layers, with possible applications for micro-patterns fabrication through an appropriate fiber arrangement.

Osmotic stress affects functional properties of human melanoma cell lines

Understanding the role of microenvironment in cancer growth and metastasis is a key issue for cancer research. Here, we study the effect of osmotic pressure on the functional properties of primary and metastatic melanoma cell lines. In particular, we experimentally quantify individual cell motility and transmigration capability. We then perform a circular scratch assay to study how a cancer cell front invades an empty space. Our results show that primary melanoma cells are sensitive to a low osmotic pressure, while metastatic cells are less. To better understand the experimental results, we introduce and study a continuous model for the dynamics of a cell layer and a stochastic discrete model for cell proliferation and diffusion. The two models capture essential features of the experimental results and allow to make predictions for a wide range of experimentally measurable parameters.

Chemotaxis migration and morphogenesis of living colonies.

Abstract.Development of forms in living organisms is complex and fascinating. Morphogenetic theories that investigate these shapes range from discrete to continuous models, from the variational elasticity to time-dependent fluid approach. Here a mixture model is chosen to describe the mass transport in a morphogenetic gradient: it gives a mathematical description of a mixture involving several constituents in mechanical interactions. This model, which is highly flexible can incorporate many biological processes but also complex interactions between cells as well as between cells and their environment. We use this model to derive a free-boundary problem easier to handle analytically. We solve it in the simplest geometry: an infinite linear front advancing with a constant velocity. In all the cases investigated here as the 3 D diffusion, the increase of mitotic activity at the border, nonlinear laws for the uptake of morphogens or for the mobility coefficient, a planar front exists above a critical threshold for the mobility coefficient but it becomes unstable just above the threshold at long wavelengths due to the existence of a Goldstone mode. This explains why sparsely bacteria exhibit dendritic patterns experimentally in opposition to other colonies such as biofilms and epithelia which are more compact. In the most unstable situation, where all the laws: diffusion, chemotaxis driving and chemoattractant uptake are linear, we show also that the system can recover a dynamic stability. A second threshold for the mobility exists which has a lower value as the ratio between diffusion coefficients decreases. Within the framework of this model where the biomass is treated mainly as a viscous and diffusive fluid, we show that the multiplicity of independent parameters in real biologic experimental set-up may explain varieties of observed patterns.Graphical abstract