Biology subjects

Khalilgharibi, N.

Publications and source records attributed to Khalilgharibi, N..

8 recordsLinked to original sources

bioRxiv2026

Basement membrane sets the timescale of tissue mechanical memory

The basement membrane (BM) is a specialised extracellular matrix tightly tethered to epithelial tissues. While the viscoelastic response of epithelial cells to external deformation has been widely studied, the dynamic mechanical role of its underlying BM remains poorly understood. This is mainly due to its thin, dense, non-fibrillar structure and limited number of model systems that allow live fluorescent imaging of the BM components. Using the Drosophila wing disc, we investigate the BMs response to sustained deformation and find that the tissue retains memory of its shape for up to four hours, enabled by the BMs initial elasticity. However, prolonged deformation leads to BM network rearrangement and loss of mechanical memory, resulting in permanent shape change. Our findings reveal that the BM sets the long-term viscoelastic timescale of epithelial tissues which plays a critical role in maintaining tissue architecture under mechanical stress.

biophysics↗

bioRxiv2024

Non-equilibrium remodelling of collagen-IV networks in silico

Collagen IV is one of the main components of the basement membrane, a layer of material that lines the majority of tissues in multicellular organisms. Collagen-IV molecules assemble into networks, providing stiffness and elasticity to tissues and informing cell and organ shape, especially during development. In this work, we develop two coarse grained models for collagen-IV molecules that retain biochemical bond specificity and coarse-grain at different length scales. Through molecular dynamics simulations, we test the assembly and mechanics of the resulting networks and measure their response to strain in terms of stress, microscopic alignment, and bond dynamics. Within the basement membrane, collagen-IV networks rearrange by molecule turnover, which affects tissue organisation and can be linked with enzyme activity. Here we explore network rearrangements via bond remodelling -- the process of dynamical breaking and remaking of bonds between network molecules. We then investigate the effects of active (enzymatic) bond remodelling. We find that this non-equilibrium remodelling allows a network to keep its integrity under strain, while relaxing fully over a variety of timescales - a dynamic response that is unavailable to networks undergoing equilibrium remodelling.

biophysics↗

bioRxiv2024

Local weakening of cell-ECM adhesion triggers basal tissue folding via changes in cell shape, actomyosin organization and E-cad levels

During development, epithelial sheets sculpt organs by folding, either apically or basally, into complex 3D structures. Given the presence of actomyosin networks and cell adhesion sites on both sides of cells, a common machinery mediating apical and basal epithelial tissue folding has been proposed. However, little is known about the mechanisms regulating epithelial folding towards the basal side. Here, using the Drosophila wing imaginal disc and a multidisciplinary approach, combining genetic perturbations and computational modelling, we demonstrate opposing roles for cell-cell and cell-ECM adhesion systems during epithelial folding. Thus, while cadherin-mediated adhesion, linked to actomyosin network, regulates apical folding, a reduction on integrin-dependent adhesion, followed by changes in cell shape, organization of the basal actomyosin cytoskeleton and E-Cad levels, is necessary and sufficient to trigger basal folding. These results suggest that modulation of the cell mechanical landscape through the crosstalk between integrins and cadherins is essential for correct epithelial folding.

developmental biology↗

bioRxiv2019

Curling of epithelial monolayers reveals coupling between active bending and tissue tension

Epithelial monolayers are two-dimensional cell sheets which compartmentalise the body and organs of multi-cellular organisms. Their morphogenesis during development or pathology results from patterned endogenous and exogenous forces and their interplay with tissue mechanical properties. In particular, bending of epithelia is thought to results from active torques generated by the polarization of myosin motors along their apico-basal axis. However, the contribution of these out-of-plane forces to morphogenesis remains challenging to evaluate because of the lack of direct mechanical measurement. Here, we use epithelial curling to characterize the out-of-plane mechan ics of epithelial monolayers. We find that curls of high curvature form spontaneously at the free edge of epithelial monolayers devoid of substrate in vivo and in vitro. Curling originates from an enrichment of myosin in the basal domain that generates an active spontaneous curvature. By measuring the force necessary to flatten curls, we can then estimate the active torques and the bending modulus of the tissue. Finally, we show that the extent of curling is controlled by the interplay between in-plane and out-of-plane stresses in the monolayer. Such mechanical coupling implies an unexpected role for in-plane stresses in shaping epithelia during morphogenesis.

biophysics↗

bioRxiv2019

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 gives often rise to a distinctive power-law regime. 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 can be derived from the model parameters, and together these explain different qualitative behaviours observed in creep after genetic and chemical treatments. 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 for diagnostic methods based on mechanical traits as well as more accurate computational models of tissues mechanics.

biophysics↗

bioRxiv2018

Actomyosin controls planarity and folding of epithelia in response to compression

Throughout embryonic development and adult life, epithelia are subjected to external forces. The resulting deformations can have a profound impact on tissue development and function. These include compressive deformations which, although hard to study in model systems due to the confounding effects of the substrate, are thought to play an important role in tissue morphogenesis by inducing tissue folding and by triggering mechanosensitive responses including cell extrusion and cell differentiation. Here, using suspended epithelia, we are able to uncover the immediate response of epithelial tissues to the application of large (5-80%) in-plane compressive strains. We show that fast compression induces tissue buckling followed by active tissue flattening which erases the buckle within tens of seconds. Strikingly, there is a well-defined limit to this second response, so that stable folds form in the tissue for compressive strains larger than [~]35%. Finally, a combination of experiment and modelling shows that the response to compression is orchestrated by the automatic adaptation of the actomyosin cytoskeleton as it re-establishes tension in compressed tissues. Thus, tissue pre-tension allows epithelia to both buffer against fast compression and regulate folding.

biophysics↗

bioRxiv2018

Stress relaxation in epithelial monolayers is controlled by actomyosin

Epithelial monolayers are one-cell thick tissue sheets that separate internal and external environments. As part of their function, they withstand extrinsic mechanical stresses applied at high strain rate. However, little is known about how monolayers respond to mechanical deformations. In stress relaxation tests, monolayers respond in a biphasic manner and stress dissipation is accompanied by an increase in monolayer resting length, pointing to active remodelling of cell architecture during relaxation. Consistent with this, actomyosin remodels at a rate commensurate with mechanical relaxation and governs the rate of monolayer stress relaxation - as in single cells. By contrast, junctional complexes and intermediate filaments form stable connections between cells, enabling monolayers to behave rheologically as single cells. Together, these data show actomyosin cytoskeletal dynamics govern the rheological properties of monolayers by enabling active, ATP-dependent changes in the resting length. These findings have far-reaching consequences for our understanding of developmental morphogenesis and tissue response to mechanical stress.

biophysics↗

bioRxiv2017

Polarization of Myosin II refines tissue material properties to buffer mechanical stress.

As tissues develop, they are subjected to a variety of mechanical forces. Some of these forces, such as those required for morphogenetic movements, are instrumental to the development and sculpting of tissues. However, mechanical forces can also lead to accumulation of substantial tensile stress, which if maintained, can result in tissue damage and impair tissue function. Despite our extensive understanding of force-guided morphogenesis, we have only a limited understanding of how tissues prevent further morphogenesis, once shape is determined after development. Buffering forces to prevent cellular changes in response to fluctuations of mechanical stress is critical during the lifetime of an adult organism. Here, through the development of a novel tissue-stretching device, we uncover a mechanosensitive pathway that regulates tissue responses to mechanical stress through the polarization of Myosin II across the tissue. Mechanistically, this process is independent of conserved Rho-kinase signaling but is mediated by force-induced linear actin polymerization and depolymerization via the formin Diaphanous and actin severing protein Cofilin, respectively. Importantly, these stretch-induced actomyosin cables stiffen the tissue to limit changes in cell shape and to protect the tissue from further mechanical damage prior to stress dissipation. This tissue rigidification prevents fractures in the tissue from propagating by confining the damage locally to the injured cells. Overall this mechanism of force-induced changes in tissue mechanical properties provides a general model of force buffering that rapidly protects tissues from physical damage to preserve tissue shape.

biophysics↗