UMR168 – Laboratoire Physico-Chimie Curie

Publications de l’UMR 168

Année de publication : 2018

Merle T, Farge E. (2018 Aug 1)

Trans-scale mechanotransductive cascade of biochemical and biomechanical patterning in embryonic development: the light side of the force.

Curr. Opin. Cell. Biol. : DOI : 10.1016/j.ceb.2018.07.003 En savoir plus
Résumé

Embryonic development is made of complex tissue shape changes and cell differentiation tissue patterning. Both types of morphogenetic processes, respectively biomechanical and biochemical in nature, were historically long considered as disconnected. Evidences of the biochemical patterning control of morphogenesis accumulated during the last 3 decades. Recently, new data revealed reversal mechanotransductive feedback demonstrating the strong coupling between embryonic biomechanical and biochemical patterning. Here we will review the findings of the emerging field of mechanotransduction in animal developmental biology and its most recent advancements. We will see how such mechanotransductive cascade of biochemical and mechanical patterning events ensures trans-scale direct cues of co-regulation of the microscopic biomolecular activities with the macroscopic morphological patterning. Mechanotransduction regulates many aspects of embryonic development including efficient collective cell behaviour, distant tissues morphogenesis coordination, and the robust coordination of tissue shape morphogenesis with differentiation.

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Simon C, Caorsi V, Campillo C, Sykes C (2018 Jul 30)

Interplay between membrane tension and the actin cytoskeleton determines shape changes

Physical Biology : 5 : 065004 : DOI : 10.1088/1478-3975/aad1ab En savoir plus
Résumé

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Röper Jens-Christian, Mitrossilis Démosthène, Stirnemann Guillaume, Waharte François, Brito Isabel, Fernandez-Sanchez Maria-Elena, Baaden Marc, Salamero Jean, Farge Emmanuel (2018 Jul 19)

The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation in vivo

eLIFE : 7:e33381. DOI: https://doi.org/10.7554/eLife.33381 : DOI : DOI: https://doi.org/10.7554/eLife.33381 En savoir plus
Résumé

In vivo, the primary molecular mechanotransductive events mechanically initiating cell differentiation remain unknown. Here we find the molecular stretching of the highly conserved Y654-beta-catenin-D665-E-cadherin binding site as mechanically induced by tissue strain. It triggers the increase of accessibility of the Y654 site, target of the Src42A kinase phosphorylation leading to irreversible unbinding. Molecular dynamics simulations of the beta-catenin/E-cadherin complex under a force mimicking a 6 pN physiological mechanical strain predict a local 45% stretching between the two a-helices linked by the site and a 15% increase in accessibility of the phosphorylation site. Both are quantitatively observed using FRET lifetime imaging and non-phospho Y654 specific antibody labelling, in response to the mechanical strains developed by endogenous and magnetically mimicked early mesoderm invagination of gastrulating Drosophila embryos. This is followed by the predicted release of 16% of beta-catenin from junctions, observed in FRAP, which initiates the mechanical activation of the b-catenin pathway process.

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Duclos G., Deforet M., Yevick H.G., Cochet-Escartin O., Ascione F., Moitrier S., Sarkar T., Yashunsky V., Bonnet I., Buguin A., Silberzan P. (2018 Jun 11)

Controlling confinement and topology to study collective cell behaviors

Methods in Molecular Biology“Cell Migration: Methods and Protocols” : 1749 : 387-399 : DOI : 10.1007/978-1-4939-7701-7_28 En savoir plus
Résumé

Confinement and substrate topology strongly affect the behavior of cell populations and, in particular, their collective migration. In vitro experiments dealing with these aspects require strategies of surface patterning that remain effective over long times (typically several days) and ways to control the surface topology in three dimensions. Here, we describe protocols addressing these two aspects. High-resolution patterning of a robust cell-repellent coating is achieved by etching the coating through a photoresist mask patterned directly on the coated surface. Out-of-plane curvature can be controlled using glass wires or corrugated « wavy » surfaces.

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Broders-Bondon Florence, Nguyen Ho-Bouldoires Thanh, Fernandez-Sanchez Maria Elena-Farge Emmanuel (2018 May 17)

Mechanotransduction in tumor progression: The dark side of the force.

Journal of Cell Biology : 217(5):1571-1587 : DOI : 10.1083/jcb.201701039 En savoir plus
Résumé

Cancer has been characterized as a genetic disease, associated with mutations that cause pathological alterations of the cell cycle, adhesion, or invasive motility. Recently, the importance of the anomalous mechanical properties of tumor tissues, which activate tumorigenic biochemical pathways, has become apparent. This mechanical induction in tumors appears to consist of the destabilization of adult tissue homeostasis as a result of the reactivation of embryonic developmental mechanosensitive pathways in response to pathological mechanical strains. These strains occur in many forms, for example, hypervascularization in late tumors leads to high static hydrodynamic pressure that can promote malignant progression through hypoxia or anomalous interstitial liquid and blood flow. The high stiffness of tumors directly induces the mechanical activation of biochemical pathways enhancing the cell cycle, epithelial–mesenchymal transition, and cell motility. Furthermore, increases in solid-stress pressure associated with cell hyperproliferation activate tumorigenic pathways in the healthy epithelial cells compressed by the neighboring tumor. The underlying molecular mechanisms of the translation of a mechanical signal into a tumor inducing biochemical signal are based on mechanically induced protein conformational changes that activate classical tumorigenic signaling pathways. Understanding these mechanisms will be important for the development of innovative treatments to target such mechanical anomalies in cancer.

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Jérémie Barral, Frank Jülicher, Pascal Martin (2018 Feb 6)

Friction from Transduction Channels’ Gating Affects Spontaneous Hair-Bundle Oscillations.

Biophysical journal : 425-436 : DOI : S0006-3495(17)31251-1 En savoir plus
Résumé

Hair cells of the inner ear can power spontaneous oscillations of their mechanosensory hair bundle, resulting in amplification of weak inputs near the characteristic frequency of oscillation. Recently, dynamic force measurements have revealed that delayed gating of the mechanosensitive ion channels responsible for mechanoelectrical transduction produces a friction force on the hair bundle. The significance of this intrinsic source of dissipation for the dynamical process underlying active hair-bundle motility has remained elusive. The aim of this work is to determine the role of friction in spontaneous hair-bundle oscillations. To this end, we characterized key oscillation properties over a large ensemble of individual hair cells and measured how viscosity of the endolymph that bathes the hair bundles affects these properties. We found that hair-bundle movements were too slow to be impeded by viscous drag only. Moreover, the oscillation frequency was only marginally affected by increasing endolymph viscosity by up to 30-fold. Stochastic simulations could capture the observed behaviors by adding a contribution to friction that was 3-8-fold larger than viscous drag. The extra friction could be attributed to delayed changes in tip-link tension as the result of the finite activation kinetics of the transduction channels. We exploited our analysis of hair-bundle dynamics to infer the channel activation time, which was ∼1 ms. This timescale was two orders-of-magnitude shorter than the oscillation period. However, because the channel activation time was significantly longer than the timescale of mechanical relaxation of the hair bundle, channel kinetics affected hair-bundle dynamics. Our results suggest that friction from channel gating affects the waveform of oscillation and that the channel activation time can tune the characteristic frequency of the hair cell. We conclude that the kinetics of transduction channels’ gating plays a fundamental role in the dynamic process that shapes spontaneous hair-bundle oscillations.

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Sherwood DR, Plastino J (2018 Jan 1)

Invading, leading and navigating cells in Caenorhabditis elegans: insights into cell movement in vivo

Genetics : 208 : 53-78 : DOI : 10.1534/genetics.117.300082 En savoir plus
Résumé

Highly regulated cell migration events are crucial during animal tissue formation and the trafficking of cells to sites of infection and injury. Misregulation of cell movement underlies numerous human diseases, including cancer. Although originally studied primarily in two-dimensional in vitro assays, most cell migrations in vivo occur in complex three-dimensional tissue environments that are difficult to recapitulate in cell culture or ex vivo Further, it is now known that cells can mobilize a diverse repertoire of migration modes and subcellular structures to move through and around tissues. This review provides an overview of three distinct cellular movement events in Caenorhabditis eleganscell invasion through basement membrane, leader cell migration during organ formation, and individual cell migration around tissues-which together illustrate powerful experimental models of diverse modes of movement in vivo We discuss new insights into migration that are emerging from these in vivo studies and important future directions toward understanding the remarkable and assorted ways that cells move in animals.

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Année de publication : 2017

Francesco Gianoli, Thomas Risler, Andrei S. Kozlov (2017 Dec 19)

Lipid bilayer mediates ion-channel cooperativity in a model of hair-cell mechanotransduction

Proceedings of the National Academy of Sciences of the United States of America : 114 : E11010-E11019 : DOI : 10.1073/pnas.1713135114 En savoir plus
Résumé

Mechanoelectrical transduction in the inner ear is a biophysical process underlying the senses of hearing and balance. The key players involved in this process are mechanosensitive ion channels. They are located in the stereocilia of hair cells and opened by the tension in specialized molecular springs, the tip links, connecting adjacent stereocilia. When channels open, the tip links relax, reducing the hair-bundle stiffness. This gating compliance makes hair cells especially sensitive to small stimuli. The classical explanation for the gating compliance is that the conformational rearrangement of a single channel directly shortens the tip link. However, to reconcile theoretical models based on this mechanism with experimental data, an unrealistically large structural change of the channel is required. Experimental evidence indicates that each tip link is a dimeric molecule, associated on average with two channels at its lower end. It also indicates that the lipid bilayer modulates channel gating, although it is not clear how. Here, we design and analyze a model of mechanotransduction where each tip link attaches to two channels, mobile within the membrane. Their states and positions are coupled by membrane-mediated elastic forces arising from the interaction between the channels’ hydrophobic cores and that of the lipid bilayer. This coupling induces cooperative opening and closing of the channels. The model reproduces the main properties of hair-cell mechanotransduction using only realistic parameters constrained by experimental evidence. This work provides an insight into the fundamental role that membrane-mediated ion-channel cooperativity can play in sensory physiology.

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Win Pin Ng, Kevin D. Webster, Caroline Stefani, Eva M. Schmid, Emmanuel Lemichez, Patricia Bassereau, Daniel A. Fletcher (2017 Oct 2)

Force-induced transcellular tunnel formation in endothelial cells

Molecular Biology of the Cell : 28 : 2650-2660 : DOI : 10.1091/mbc.E17-01-0080 En savoir plus
Résumé

The endothelium serves as a protective semipermeable barrier in blood vessels and lymphatic vessels. Leukocytes and pathogens can pass directly through the endothelium by opening holes in endothelial cells, known as transcellular tunnels, which are formed by contact and self-fusion of the apical and basal plasma membranes. Here we test the hypothesis that the actin cytoskeleton is the primary barrier to transcellular tunnel formation using a combination of atomic force microscopy and fluorescence microscopy of live cells. We find that localized mechanical forces are sufficient to induce the formation of transcellular tunnels in human umbilical vein endothelial cells (HUVECs). When HUVECs are exposed to the bacterial toxin called epidermal cell differentiation inhibitor (EDIN), which can induce spontaneous transcellular tunnels, less mechanical work is required to form tunnels due to the reduced cytoskeletal stiffness and thickness of these cells, similarly to the effects of a Rho-associated protein kinase (ROCK) inhibitor. We also observe actin enrichment in response to mechanical indentation that is reduced in cells exposed to the bacterial toxin. Our study shows that the actin cytoskeleton of endothelial cells provides both passive and active resistance against transcellular tunnel formation, serving as a mechanical barrier that can be overcome by mechanical force as well as disruption of the cytoskeleton.

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Shunsuke Yabunaka, Philippe Marcq (2017 Sep 28)

Cell growth, division, and death in cohesive tissues: A thermodynamic approach.

Physical review. E : 022406 : DOI : 10.1103/PhysRevE.96.022406 En savoir plus
Résumé

Cell growth, division, and death are defining features of biological tissues that contribute to morphogenesis. In hydrodynamic descriptions of cohesive tissues, their occurrence implies a nonzero rate of variation of cell density. We show how linear nonequilibrium thermodynamics allows us to express this rate as a combination of relevant thermodynamic forces: chemical potential, velocity divergence, and activity. We illustrate the resulting effects of the nonconservation of cell density on simple examples inspired by recent experiments on cell monolayers, considering first the velocity of a spreading front, and second an instability leading to mechanical waves.

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Shuji Ishihara, Philippe Marcq, Kaoru Sugimura (2017 Sep 28)

From cells to tissue: A continuum model of epithelial mechanics.

Physical review. E : 022418 : DOI : 10.1103/PhysRevE.96.022418 En savoir plus
Résumé

A two-dimensional continuum model of epithelial tissue mechanics was formulated using cellular-level mechanical ingredients and cell morphogenetic processes, including cellular shape changes and cellular rearrangements. This model incorporates stress and deformation tensors, which can be compared with experimental data. Focusing on the interplay between cell shape changes and cell rearrangements, we elucidated dynamical behavior underlying passive relaxation, active contraction-elongation, and tissue shear flow, including a mechanism for contraction-elongation, whereby tissue flows perpendicularly to the axis of cell elongation. This study provides an integrated scheme for the understanding of the orchestration of morphogenetic processes in individual cells to achieve epithelial tissue morphogenesis.

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Plastino J, Blanchoin L (2017 Sep 25)

Adaptive actin networks

Developmental Cell : 42 : 565-566 : DOI : 10.1016/j.devcel.2017.09.005 En savoir plus
Résumé

Despite their fundamental importance in the regulation of cell physiology, the mechanisms that confer cell adaptability to changes in the microenvironment are poorly understood. A recent study in Cell (Mueller et al., 2017) examines the capability of branched actin networks to respond and adapt to mechanical load in vivo.

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Rückerl F, Lenz M, Betz T, Manzi J, Martiel J-L, Safouane M, Paterski-Boujemaa R, Blanchoin L, Sykes C (2017 Sep 5)

Adaptive response of actin bundles under mechanical stress

Biophysical Journal : 113 : 1072-1079 : DOI : 10.1016/j.bpj.2017.07.017 En savoir plus
Résumé

Actin is one of the main components of the architecture of cells. Actin filaments form different polymer networks with versatile mechanical properties that depend on their spatial organization and the presence of cross-linkers. Here, we investigate the mechanical properties of actin bundles in the absence of cross-linkers. Bundles are polymerized from the surface of mDia1-coated latex beads, and deformed by manipulating both ends through attached beads held by optical tweezers, allowing us to record the applied force. Bundle properties are strikingly different from the ones of a homogeneous isotropic beam. Successive compression and extension leads to a decrease in the buckling force that we attribute to the bundle remaining slightly curved after the first deformation. Furthermore, we find that the bundle is solid, and stiff to bending, along the long axis, whereas it has a liquid and viscous behavior in the transverse direction. Interpretation of the force curves using a Maxwell visco-elastic model allows us to extract the bundle mechanical parameters and confirms that the bundle is composed of weakly coupled filaments. At short times, the bundle behaves as an elastic material, whereas at long times, filaments flow in the longitudinal direction, leading to bundle restructuring. Deviations from the model reveal a complex adaptive rheological behavior of bundles. Indeed, when allowed to anneal between phases of compression and extension, the bundle reinforces. Moreover, we find that the characteristic visco-elastic time is inversely proportional to the compression speed. Actin bundles are therefore not simple force transmitters, but instead, complex mechano-transducers that adjust their mechanics to external stimulation. In cells, where actin bundles are mechanical sensors, this property could contribute to their adaptability.

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Shunsuke Yabunaka, Philippe Marcq (2017 Aug 30)

Emergence of epithelial cell density waves.

Soft matter : DOI : 10.1039/c7sm01172e En savoir plus
Résumé

Epithelial cell monolayers exhibit traveling mechanical waves. We rationalize this observation thanks to a hydrodynamic description of the monolayer as a compressible, active and polar material. We show that propagating waves of the cell density, polarity, velocity and stress fields may be due to a Hopf bifurcation occurring above threshold values of active coupling coefficients.

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Breau M, Bonnet I, Stoufflet J, Xie J, De Castro S, Schneider-Maunoury S (2017 Aug 21)

Extrinsic mechanical forces mediate retrograde axon extension in a developing neuronal circuit

Nature Communications : 8 : 282 : DOI : 10.1038/s41467-017-00283-3 En savoir plus
Résumé

To form functional neural circuits, neurons migrate to their final destination and extend axons towards their targets. Whether and how these two processes are coordinated in vivo remains elusive. We use the zebrafish olfactory placode as a system to address the underlying mechanisms. Quantitative live imaging uncovers a choreography of directed cell movements that shapes the placode neuronal cluster: convergence of cells towards the centre of the placodal domain and lateral cell movements away from the brain. Axon formation is concomitant with lateral movements and occurs through an unexpected, retrograde mode of extension, where cell bodies move away from axon tips attached to the brain surface. Convergence movements are active, whereas cell body lateral displacements are of mainly passive nature, likely triggered by compression forces from converging neighbouring cells. These findings unravel a previously unknown mechanism of neuronal circuit formation, whereby extrinsic mechanical forces drive the retrograde extension of axons.

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