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The inherent membrane tension of biological materials could vitally affect their responses to contact loading but is generally ignored in existing indentation analysis. In this paper, the authors theoretically investigate the contact stiffness of axisymmetric indentations of elastic solids covered with thin tensed membranes. When the indentation size decreases to the same order as the ratio of membrane tension to elastic modulus, the contact stiffness accounting for the effect of membrane tension becomes much higher than the prediction of conventional contact theory. An explicit expression is derived for the contact stiffness, which is universal for axisymmetric indentations using indenters of arbitrary convex profiles. On this basis, a simple method of analysis is proposed to estimate the membrane tension and elastic modulus of biological materials from the indentation load-depth data, which is successfully applied to analyze the indentation experiments of cells and lungs. This study might be helpful for the comprehensive assessment of the mechanical properties of soft biological systems. This paper highlights the crucial effect of the inherent membrane tension on the indentation response of soft biomaterials, which has been generally ignored in existing analysis of experiments. For typical indentation tests on cells and organs, the contact stiffness can be twice or higher than the prediction of conventional contact model. A universal expression of the contact stiffness accounting for the membrane tension effect is derived. On this basis, a simple method of analysis is proposed to abstract the membrane tension of biomaterials from the experimentally recorded indentation load-depth data. With this method, the elasticity of soft biomaterials can be characterized more comprehensively. [Display omitted] [ABSTRACT FROM AUTHOR]

Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity. Vincristine leads to the swelling of DRG neurons, increases their membrane tension and promotes PIEZO2 channel membrane trafficking, which results in the potentiation of PIEZO2 mechanically-activated currents, thereby mediates vincristine-induced mechanical hypersensitivity. [Display omitted] [ABSTRACT FROM AUTHOR]

Endocytic traffic is a complex and elegant operation involving cargo sorting, membrane budding and tubulation, generation of force, and the formation of organellar contacts. The role of specific proteins and lipids in these processes has been studied extensively. By comparison, precious little is understood about the contribution of the endocytic fluid to these events, despite much evidence that alteration of the contents can severely affect membrane traffic along the endocytic pathway. In particular, it has long been appreciated that dissipation of ionic gradients arrests endosome-to-lysosome maturation. How cells sense inorganic ions and transmit this information have remained largely enigmatic. Herein, we review the experimental findings that reveal an intimate association between luminal ions, their transport, and endocytic traffic. We then discuss the ionic sensors and the mechanisms proposed to convert ion concentrations into protein-based trafficking events, highlighting the current paucity of convincing explanations. [ABSTRACT FROM AUTHOR]

The budding of membranes and curvature generation is common to many forms of trafficking in cells. Clathrin-mediated endocytosis, as a prototypical example of trafficking, has been studied in great detail using a variety of experimental systems and methods. Recently, advances in experimental methods have led to great strides in insights on the molecular mechanisms and the spatiotemporal dynamics of the protein machinery associated with membrane curvature generation. These advances have been ably supported by computational models, which have given us insights into the underlying mechanical principles of clathrin-mediated endocytosis. On the other hand, targeted experimental perturbation of membranes has lagged behind that of proteins in cells. In this area, modeling is especially critical to interpret experimental measurements in a mechanistic context. Here, we discuss the contributions made by these models to our understanding of endocytosis and identify opportunities to strengthen the connections between models and experiments. Model development for the different subprocesses of clathrin-mediated endocytosis (CME) can span different length scales. Like the pieces of a puzzle, these different modeling approaches at different scales contribute to our understanding of the mechanisms underlying CME. [Display omitted] • Membrane curvature generation is a readout of the underlying biomechanical events. • Computational models help identify the physical principles behind membrane budding. • Tight connection between experiments and models will aid study of design principles. • New experiments should consider how measurements can be related to model parameters. [ABSTRACT FROM AUTHOR]

The mechanical behavior of spherical capsules and red blood cells in shear and confined pressure-driven flow of polymeric fluids was studied computationally. In particular, we study the effect of suspending fluid elasticity on the steady mechanical behavior of spherical capsules and red blood cells suspended in an Oldroyd-B fluid, in dilute shear and confined pressure-driven flow, as a model system for dilute suspensions of capsules in polymeric fluids. We investigate the effects of suspending fluid elasticity at fixed capillary number on the capsule deformation, membrane tensions, and effective viscosity for a range of capsule capillary numbers. For both spherical capsules and red blood cells, capsule deformation was found to decrease with increasing fluid elasticity in shear flow, and increase in confined pressure-driven flow. The average membrane tension for spherical capsules was found to follow the same trends: decreasing in shear and increasing in pressure-driven flow; however, the average membrane tension for red blood cells had a less pronounced trend with fluid elasticity, which we attribute to the reduced volume of the red blood cell. On the other hand, the effective viscosity of the suspension was found to be non-monotonic with an increase in suspending fluid elasticity for both flows and particle types. The underlying mechanisms for these trends were investigated by comparing these capsule simulations to results from rigid spherical particles. These results indicate that the mechanical behavior of these dilute capsule suspensions can be qualitatively understood by examining the disturbance flow created by the introduction of rigid spherical particles, and the subsequent stress induced in the polymeric fluid to these disturbances. • The effects of fluid elasticity in dilute capsule suspensions are investigated • At the particle level, elasticity affects capsule deformation and membrane tension • Elasticity also affects the bulk rheology (effective viscosity) of the suspension • Compared against rigid particle-fluid interactions in viscoelastic flow [ABSTRACT FROM AUTHOR]

Phagocytosis is a widespread and evolutionarily conserved process with diverse biological functions, ranging from engulfment of invading microbes during infection to clearance of apoptotic debris in tissue homeostasis. Along with differences in biochemical composition, phagocytic targets greatly differ in physical attributes, such as size, shape, and rigidity, which are now recognized as important regulators of this process. Force exertion at the cell–target interface and cellular mechanical changes during phagocytosis are emerging as crucial factors underlying sensing of such target properties. With technological developments, mechanical aspects of phagocytosis are increasingly accessible experimentally, revealing remarkable organizational complexity of force exertion. An increasingly high-resolution picture is emerging of how target physical cues and cellular mechanical properties jointly govern important steps throughout phagocytic engulfment. • Cytoskeletal forces, cytoplasmic viscosity, membrane tension, and cortical tension are key regulators of phagocytosis. • Cellular force exertion during phagocytosis shows complex spatiotemporal patterns, inconsistent with a simple zipper model. • Phagocytic targets widely differ in their rigidity, which is a crucial regulator of phagocytosis in the 0.1-100 kPa range. • Target geometry is a complex parameter, wihch can regulate phagocytosis through local and global shape cues. [ABSTRACT FROM AUTHOR]

The cell surface is a mechanobiological unit that encompasses the plasma membrane, its interacting proteins, and the complex underlying cytoskeleton. Recently, attention has been directed to the mechanics of the plasma membrane, and in particular membrane tension, which has been linked to diverse cellular processes such as cell migration and membrane trafficking. However, how tension across the plasma membrane is regulated and propagated is still not completely understood. Here, we review recent efforts to study the interplay between membrane tension and the cytoskeletal machinery and how they control cell form and function. We focus on factors that have been proposed to affect the propagation of membrane tension and as such could determine whether it can act as a global or local regulator of cell behavior. Finally, we discuss the limitations of the available tool kit as new approaches that reveal its dynamics in cells are needed to decipher how membrane tension regulates diverse cellular processes. [ABSTRACT FROM AUTHOR]

The yeast plasma membrane is a selective barrier between an erratic environment and the cell's metabolism. Nutrient transporters are the gatekeepers that control the import of molecules feeding into the metabolic pathways. Nutrient import adjusts rapidly to changes in metabolism and the environment, which is accomplished by regulating the surface expression of transporters. Recent studies indicate that the lipid environment in which transporters function regulates ubiquitination efficiency and endocytosis of these proteins. Changes in the lipid environment are caused by lateral movements of the transporters between different membrane domains and by the influence of the extracellular environment on the fluidity of the plasma membrane. [ABSTRACT FROM AUTHOR]

Using nanostructured substrates for enhancing cell adhesion is an important method. However, the physical mechanism of cell adhesion on nanostructured substrate is not well understood yet, particularly the evolution process of membrane during cell adhesion. Here, we propose an analytical model to study quantitatively the evolution of membrane during adhesion process on the nanostructured substrate. The effects of substrate surface topography, receptor-ligand binding, substrate property and membrane property were investigated. We found a small nanopillar radius, low nanopillar density, large binding rate, large receptor density, low non-specific energy, or large stretching modulus can result in a large adhesion rate and a large adhesion depth. Besides, the evolution of membrane on truncated nanocone arrays was also studied by the model. The theoretical results are in good agreement with the experimental observations, which implied that our studies can provide a useful guide to control cell adhesion process and cell motion on nanostructured substrates. • We established a model to study cell adhesion on nanostructured substrate. • The effects of receptor-ligand binding are investigated. • The effects of substrate surface topography were investigated. • The model explains adhesion depth of cell membrane in experiments. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum acts as a protein quality control center where a range of chaperones and foldases facilitates protein folding. IRE1 is a sensory transmembrane protein that transduces signals of proteotoxic stress by forming clusters and activating a cellular program called the unfolded protein response (UPR). Recently, membrane thickness variation due to membrane compositional changes have been shown to drive IRE1 cluster formation, activating the UPR even in the absence of proteotoxic stress. Here, we demonstrate a direct relationship between bilayer tension and UPR activation based on IRE1 dimer stability. The stability of the IRE1 dimer in a (50%DOPC-50%POPC) membrane at different applied bilayer tensions was analyzed via molecular dynamics simulations. The potential of mean force for IRE1 dimerization predicts a higher concentration of IRE1 dimers for both tensed and compressed ER membranes. This study shows that IRE1 may be a mechanosensitive membrane protein and establishes a direct biophysical relationship between bilayer tension and UPR activation. • IRE1 dimerization potentials are calculated in mechanically perturbed membranes. • Both tension and compression promote IRE1 dimer formation. • IRE1 is potentially a mechanosensitive actuator of the unfolded protein response. [Display omitted] [ABSTRACT FROM AUTHOR]

The bacterial mechanosensitive channel of small conductance (MscS) is a well-studied model of how mechanical forces from the membrane can be sensed by an embedded protein. A recent study by Zhang et al. visualizes how MscS behaves under membrane tension, entering a desensitized state when it loses all coordinated lipids. [ABSTRACT FROM AUTHOR]

Background Cell surface mechanics is able to physically and biomechanically affect cell shape and motility, vesicle trafficking and actin dynamics. The biophysical properties of cell surface are strongly influenced by cytoskeletal elements. In mammals, tissue-specific expression of six actin isoforms is thought to confer differential biomechanical properties. However, the relative contribution of actin isoforms to cell surface properties is not well understood. Here, we sought to investigate whether and how the composition of endogenous actin isoforms directly affects the biomechanical features of cell surface and cellular behavior. Methods We used fibroblasts isolated from wild type (WT), heterozygous (HET) and from knockout (KO) mouse embryos where both β-actin alleles are not functional. We applied a combination of genome-wide analysis and biophysical methods such as RNA-seq and atomic force microscopy. Results We found that endogenous β-actin levels are essential in controlling cell surface stiffness and pull-off force, which was not compensated by the up-regulation of other actin isoforms. The variations of surface biophysical features and actin contents were associated with distinct cell behaviors in 2D and 3D WT, HET and KO cell cultures. Since β-actin in WT cells and smooth muscle α-actin up-regulated in KO cells showed different organization patterns, our data support the differential localization and organization as a mechanism to regulate the biophysical properties of cell surface by actin isoforms. Conclusions We propose that variations in actin isoforms composition impact on the biophysical features of cell surface and cause the changes in cell behavior. [ABSTRACT FROM AUTHOR]

Membrane pores can significantly alter not only the permeation dynamics of biological membranes but also their elasticity. Large membrane pores able to transport macromolecular contents represent an interesting model to test theoretical predictions that assign active-like (non-equilibrium) behavior to the permeability contributions to the enhanced membrane fluctuations existing in permeable membranes [Maneville et al. Phys. Rev. Lett. 82, 4356 (1999)]. Such high-amplitude active contributions arise from the forced transport of solvent and solutes through the open pores, which becomes even dominant at large permeability. In this paper, we present a detailed experimental analysis of the active shape fluctuations that appear in highly permeable lipid vesicles with large macromolecular pores inserted in the lipid membrane, which are a consequence of transport permeability events occurred in an osmotic gradient. The experimental results are found in quantitative agreement with theory, showing a remarkable dependence with the density of membrane pores and giving account of mechanical compliances and permeability rates that are compatible with the large size of the membrane pore considered. The presence of individual permeation events has been detected in the fluctuation time-series, from which a stochastic distribution of the permeation events compatible with a shot-noise has been deduced. The non-equilibrium character of the membrane fluctuations in a permeation field, even if the membrane pores are mere passive transporters, is clearly demonstrated. Finally, a bio-nano-technology outlook of the proposed synthetic concept is given on the context of prospective uses as active membrane DNA-pores exploitable in gen-delivery applications based on lipid vesicles. [ABSTRACT FROM AUTHOR]

Summary Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor. [ABSTRACT FROM AUTHOR]

An analytical technique is proposed for evaluating the membrane tension of the framed membranes used to protect the photomasks in I/C manufacturing. Two-dimensional wave equations relating the resonant frequency to the membrane tension are first derived. The resonant frequencies of the membrane of interest are then determined experimentally using a mechanical shaker apparatus and a chromatic confocal microscope. Finally, a trial-and-error fitting method is applied to determine the membrane tension which minimizes the error between the calculated resonant frequencies of the membrane and the experimentally-determined values. Further simulations are then performed to examine the sensitivity of the resonant frequency to the variation in membrane tension for different resonant modes and membrane dimensions. Overall, the results suggest that the analytical technique proposed in this study provides a feasible means of monitoring the pellicle quality in semiconductor wafer production by evaluating changes in its frequency response and mechanical properties. [Display omitted] • 2D wave equations relating the resonant frequency to the membrane tension are derived. • The resonant frequencies of the membrane are determined using a mechanical shaker. • Simulations are conducted to examine the frequency sensitivity to membrane tension changes. • Defective membranes are characterized by a lack of higher-order resonant frequencies. [ABSTRACT FROM AUTHOR]

Summary The conversion of mechanical force to chemical signals is critical for many biological processes, including the senses of touch, pain, and hearing. Mechanosensitive ion channels play a key role in sensing the mechanical stimuli experienced by various cell types and are present in organisms from bacteria to mammals. Bacterial mechanosensitive channels are characterized thoroughly, but less is known about their counterparts in vertebrates. Piezos have been recently established as ion channels required for mechanotransduction in disparate cell types in vitro and in vivo. Overexpression of Piezos in heterologous cells gives rise to large mechanically activated currents; however, it is unclear whether Piezos are inherently mechanosensitive or rely on alternate cellular components to sense mechanical stimuli. Here, we show that mechanical perturbations of the lipid bilayer alone are sufficient to activate Piezo channels, illustrating their innate ability as molecular force transducers. [ABSTRACT FROM AUTHOR]

The Target of Rapamycin (TOR) is a conserved serine/threonine (ser/thr) kinase that functions in two, distinct, multiprotein complexes called TORC1 and TORC2. Each complex regulates different aspects of eukaryote growth: TORC1 regulates cell volume and/or mass by influencing protein synthesis and turnover, while TORC2, as detailed in this review, regulates cell surface area by influencing lipid production and intracellular turgor. TOR complexes function in feedback loops, implying that downstream effectors are also likely to be involved in upstream regulation. In this regard, the notion that TORCs function primarily as mediators of cellular and organismal homeostasis is fundamentally different from the current, predominate view of TOR as a direct transducer of extracellular biotic and abiotic signals. [ABSTRACT FROM AUTHOR]

Cellular mechanics plays a crucial role in many biological processes such as cell migration, cell growth, embryogenesis, and oncogenesis. Epithelia respond to environmental cues comprising biochemical and physical stimuli through defined changes in cell elasticity. For instance, cells can differentiate between certain properties such as viscoelasticity or topography of substrates by adapting their own elasticity and shape. A living cell is a complex viscoelastic body that not only exhibits a shell architecture composed of a membrane attached to a cytoskeleton cortex but also generates contractile forces through its actomyosin network. Here we review cellular mechanics of single cells in the context of epithelial cell layers responding to chemical and physical stimuli. This article is part of a Special Issue entitled: Mechanobiology. [ABSTRACT FROM AUTHOR]

Wounding leads not only to plasma membrane disruption, but also to compromised cytoskeleton structures. This results not only in unwarranted exchanges between the cytosol and extracellular milieu, but also in loss of tensegrity, which may further endanger the cell. Tensegrity can be described as the interplay between the tensile forces generated by the apparent membrane tension, actomyosin contraction, and the cytoskeletal structures resisting those changes (e.g., microtubules). It is responsible for the structural integrity of the cell and for its ability to sense mechanical signals. Recent reviews dealing with single-cell healing mostly focused on the molecular machineries controlling the traffic and fusion of specific vesicles, or their role in different pathologies. In this review, we aim to take a broader view of the different modes of single cell repair, while focussing on the different ways the changes in plasmalemma surface area and composition, plasmalemma tension, and cytoskeletal dynamics may influence and affect single-cell repair. [ABSTRACT FROM AUTHOR]

In order for the cell to function well within a multicellular system, the mechanical properties of the plasma membrane need to meet two different requirements: cell shape maintenance and rearrangement. To achieve these goals, phosphoinositides play key roles in the regulation of the cortical actin cytoskeleton. PI(4,5)P 2 is the most abundant phosphoinositide species in the plasma membrane. It maintains cell shape by linking the actin cortex to the membrane via interactions with Ezrin/Radixin/Moesin (ERM) proteins and class I myosins. Although the role of D3-phosphoinositides, such as PI(3,4,5)P 3 , in actin-driven cell migration has been a subject of controversy, it becomes evident that the dynamic turnover of the phosphoinositide by the action of metabolizing enzymes, such as 5-phosphatases, is necessary. Recent studies have revealed an important role of PI(3,4)P 2 in podosome/invadopodia formation, shedding new light on the actin-based organization of membrane structures regulated by phosphoinositide signaling. This article is part of a Special Issue entitled Phosphoinositides. [ABSTRACT FROM AUTHOR]

Our understanding of the role of membrane tension in the field of membrane biophysics is rapidly evolving from a passive construct to an active player in a variety of cellular phenomena. Membrane tension has been shown to be a key regulator of many cellular processes ranging including trafficking, ion channel activation, and the invasion of red blood cells by malaria parasites. Recent experimental advances in cells, including the development of a fluorescent tension reporter, have shown that membrane tension is heterogeneous. In this mini-review, I summarize the recent advances in membrane tension measurements and discuss the contributions from different cellular constituents such as the cortical cytoskeleton. Then, I will explore how these different complexities can be considered in biophysical models of different scales. Finally, I will elaborate on the need for iterations between models and experiments as technologies in both fields advance to enable us to obtain critical insights into the physiological role of membrane tension as a critical component of mechanotransduction. • Membrane tension plays an important role in cellular processes. • Understanding the role of tension requires more modeling and experiments. • Multiscale modeling is a valuable tool for understanding tension. • Iterative feedback between experiments and modeling is important. [ABSTRACT FROM AUTHOR]

Mapping the phase behavior of multicomponent phospholipid membranes has been an ongoing pursuit, motivated by interest in both fundamental physics and cell function. Prior investigations addressed temperature-composition space and the features of the associated domains. The current study additionally considers membrane tension, analogous to pressure in bulk materials. Focusing on model mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DOPC and DPPC respectively) membranes, we examine the thermodynamic impact of tension on fluid-solid coexistence and the nature of phase-separated domains. Reported here is the 3 dimensional composition-temperature-tension phase map containing three intersecting curved surfaces. Depending on the system’s position in this 3D space, giant unilamellar vesicles containing DOPC and DPPC may exhibit, in addition to a 2-component fluid Lα phase, two different types of solid DPPC-rich domains: tracer-excluding hexagonal patches or tracer-selective stripes. The fluid phase occurs at high temperatures. At cool temperatures striped solid DPPC-rich domains coexist with the fluid at elevated tensions. These stripes occur independent of tension, at the coolest temperatures. At low tensions and intermediate temperatures, patchy solid DPPC-rich domains coexist with the Lα fluid and may persist, if kinetically trapped, at lower temperatures. We associate the striped DPPC domains with a tilt-gel (Lβ’) morphology and the hexagonal DPPC patches with a dense corrugated ripple phase (Pβ’). These assignments, based on the reported areal densities of the corrugated and tilt solids, enabled first principles estimates of the coexistence boundaries that match the experiments well, including the tension sensitivity of coexistence curves and triple-point-like features for fixed composition. [ABSTRACT FROM AUTHOR]

Abstract: Biological membranes undergo constant shape remodeling involving the formation of highly curved structures. The lipid bilayer represents the fundamental architecture of the cellular membrane with its shapes determined by the Helfrich curvature bending energy. However, the dynamics of bilayer shape transitions, especially their modulation by membrane proteins, and the resulting shape instabilities, are still not well understood. Here, we review in a unifying manner several theories that describe the fluctuations (i.e. undulations) of bilayer shapes as well as their local coupling with lipid or protein density variation. The coupling between local membrane curvature and lipid density gives rise to a ‘slipping mode’ in addition to the conventional ‘bending mode’ for damping the membrane fluctuation. This leads to a number of interesting experimental phenomena regarding bilayer shape dynamics. More importantly, curvature-inducing proteins can couple with membrane shape and eventually render the membrane unstable. A criterion for membrane shape instability is derived from a linear stability analysis. The instability criterion reemphasizes the importance of membrane tension in regulating the stability and dynamics of membrane geometry. Recent progresses in understanding the role of membrane tension in regulating dynamical cellular processes are also reviewed. Protein density is emphasized as a key factor in regulating membrane shape transitions: a threshold density of curvature coupling proteins is required for inducing membrane morphology transitions. [Copyright &y& Elsevier]

Generation of tissue curvature is essential to morphogenesis. However, how cells adapt to changing curvature is still unknown because tools to dynamically control curvature in vitro are lacking. Here, we developed self-rolling substrates to study how flat epithelial cell monolayers adapt to a rapid anisotropic change of curvature. We show that the primary response is an active and transient osmotic swelling of cells. This cell volume increase is not observed on inducible wrinkled substrates, where concave and convex regions alternate each other over short distances; and this finding identifies swelling as a collective response to changes of curvature with a persistent sign over large distances. It is triggered by a drop in membrane tension and actin depolymerization, which is perceived by cells as a hypertonic shock. Osmotic swelling restores tension while actin reorganizes, probably to comply with curvature. Thus, epithelia are unique materials that transiently and actively swell while adapting to large curvature induction. [Display omitted] • Rapid inward and outward epithelial rolling triggers cell volume increase • Epithelial folding induces a mechano-osmotic feedback loop that involvs ion channels • Cell volume regulation in curved tissues involves actin, membrane tension, and mTORC2 Tomba et al. examine the response of epithelial cells to rapid changes in curvature. They show that upon curvature induction, cell volume transiently increases while membrane tension decreases and actin depolymerizes. Actin repolymerization and membrane tension recovery restore cell volume and forces in the new curved configuration. [ABSTRACT FROM AUTHOR]

Abstract: Osmotic stress poses one of the most fundamental challenges to living cells. Particularly, the largely inextensible plasma membrane of eukaryotic cells easily ruptures under in-plane tension calling for sophisticated strategies to readily respond to osmotic stress. We describe how epithelial cells react and adapt mechanically to the exposure to hypotonic and hypertonic solutions in the context of a confluent monolayer. Site-specific indentation experiments in conjunction with tether pulling on individual cells have been carried out with an atomic force microscope to reveal spatio-temporal changes in membrane tension and surface area. We found that cells compensate for an increase in lateral tension due to hypoosmotic stress by sacrificing excess of membrane area stored in protrusions and invaginations such as microvilli and caveolae. At mild hypotonic conditions lateral tension increases partly compensated by surface are regulation, i.e. the cell sacrifices some of its membrane reservoirs. A loss of membrane–actin contacts occurs upon exposure to stronger hypotonic solutions giving rise to a drop in lateral tension. Tension release recovers on longer time scales by an increasing endocytosis, which efficiently removes excess membrane from the apical side to restore the initial pre-stress. Hypertonic solutions lead to shrinkage of cells and collapse of the apical membrane onto the cortex. Exposure to distilled water leads to stiffening of cells due to removal of excess surface area and tension increase due to elevated osmotic pressure across the plasma membrane. [Copyright &y& Elsevier]

Many cell phenomena that involve shape changes are affected by the intrinsic deformability of the plasma membrane (PM). Far from being a passive participant, the PM is now known to physically, as well as biochemically, influence cell processes ranging from vesicle trafficking to actin assembly. Here we review current understanding of how changes in PM tension regulate cell shape and movement, as well as how cells sense PM tension. [ABSTRACT FROM AUTHOR]

The generation of cell polarity is one of the most intriguing symmetry-breaking events in biology. It is involved in almost all physiological and developmental processes and, despite the differences between plant and animal cell structures, cell polarity is generated by a similar core mechanism that comprises the extracellular matrix (ECM), Rho GTPase, the cytoskeleton, and the membranes. Several recent articles show that mechanical factors also contribute to the establishment and robustness of cell polarity, and the different molecular actors of cell polarity are now viewed as integrators of both biochemical and mechanical signals. Although cell polarity remains a complex process, some level of functional convergence between plants and animals is revealed. Following comparative presentation of cell polarity in plants and animals, we will discuss the theoretical background behind the role of mechanics in polarity and the relevant experimental tests, focusing on ECM anchorage, cytoskeleton behavior, and membrane tension. [ABSTRACT FROM AUTHOR]

Abstract: The ceaseless opening and closing of the voltage-gated channels (VGCs) underlying cardiac rhythmicity is controlled, in each VGC, by four mobile voltage sensors embedded in bilayer. Every action potential necessitates extensive packing/repacking of voltage sensor domains with adjacent interacting lipid molecules. This renders VGC activity mechanosensitive (MS), i.e., energetically sensitive to the bilayer''s mechanical state. Irreversible perturbations of sarcolemmal bilayer such as those associated with ischemia, reperfusion, inflammation, cortical-cytoskeleton abnormalities, bilayer-disrupting toxins, diet aberrations, etc, should therefore perturb VGC activity. Disordered/fluidized bilayer states that facilitate voltage sensor repacking, and thus make VGC opening too easy could, therefore, explain VGC-leakiness in these conditions. To study this in membrane patches we impose mechanical blebbing injury during pipette aspiration-induced membrane stretch, a process that modulates VGC activity irreversibly (plastic regime) and then, eventually, reversibly (elastic regime). Because of differences in sensor-to-gate coupling among different VGCs, their responses to stretch fall into two major categories, MS-Speed, MS-Number, exemplified by Nav and Cav channels. For particular VGCs in perturbed bilayers, leak mechanisms depend on whether or not the rate-limiting voltage-dependent step is MS. Mode-switch transitions might also be mechanosensitive and thus play a role. Incorporated mathematically in axon models, plastic-regime Nav responses elicit ectopic firing behaviors typical of peripheral neuropathies. In cardiomyocytes with mild bleb damage, Nav and/or Cav leaks from irreversible MS modulation (MS-Speed, MS-Number, respectively) could, similarly, foster ectopic arrhythmias. Where pathologically leaky VGCs reside in damaged bilayer, peri-channel bilayer disorder/fluidity conditions could be an important “target feature” for anti-arrhythmic VGC drugs. [Copyright &y& Elsevier]

Abstract: Molecular dynamics simulations of a dioleoylphosphocholine (DOPC) lipid bilayer were performed to explore its mechanosensitivity. Variations in the bilayer properties, such as area per lipid, volume, thickness, hydration depth (HD), hydration thickness (HT), lateral diffusion coefficient, and changes in lipid structural order were computed in the membrane tension range 0 to 15dyn/cm. We determined that an increase in membrane tension results in a decrease in the bilayer thickness and HD of ~5% and ~5.7% respectively, whereas area per lipid, volume, and HT/HD increased by 6.8%, 2.4%, and 5% respectively. The changes in lipid conformation and orientation were characterized using orientational (S 2) and deuterium (S CD ) order parameters. Upon increase of membrane tension both order parameters indicated an increase in lipid disorder by 10–20%, mostly in the tail end region of the hydrophobic chains. The effect of membrane tension on lipid lateral diffusion in the DOPC bilayer was analyzed on three different time scales corresponding to inertial motion, anomalous diffusion and normal diffusion. The results showed that lateral diffusion of lipid molecules is anomalous in nature due to the non-exponential distribution of waiting times. The anomalous and normal diffusion coefficients increased by 20% and 52% when the membrane tension changed from 0 to 15dyn/cm, respectively. In conclusion, our studies showed that membrane tension causes relatively significant changes in the area per lipid, volume, polarity, membrane thickness, and fluidity of the membrane suggesting multiple mechanisms by which mechanical perturbation of the membrane could trigger mechanosensitive response in cells. [Copyright &y& Elsevier]

It has been almost 60 years since caveolae were first visualized by Eichi Yamada and George Palade. Nevertheless, these specialized invaginations of the plasma membrane remain without clear and recognized physiological function. The recent identification of new caveolar components and the ability to probe cell mechanics with sophisticated opticophysical devices have shed new light on this fascinating organelle. Early studies from the 1970s suggested that caveolae could participate in the regulation of membrane dynamics. Recent data have established caveolae as mechanosensors that respond immediately to mechanical stress by flattening into the plasma membrane. Here, we focus on the molecular consequences that result from the caveolar disassembly/reassembly cycle induced by membrane tension variations at the surface of the cell under physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Abstract: The dipole potential of lipid bilayer membrane controls the difference in permeability of the membrane to oppositely charged ions. We have combined molecular dynamics (MD) simulations and experimental studies to determine changes in electric field and electrostatic potential of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) lipid bilayer in response to applied membrane tension. MD simulations based on CHARMM36 force field showed that electrostatic potential of DOPC bilayer decreases by ~45mV in the physiologically relevant range of membrane tension values (0 to 15dyn/cm). The electrostatic field exhibits a peak (~0.8×109 V/m) near the water/lipid interface which shifts by 0.9Å towards the bilayer center at 15dyn/cm. Maximum membrane tension of 15dyn/cm caused 6.4% increase in area per lipid, 4.7% decrease in bilayer thickness and 1.4% increase in the volume of the bilayer. Dipole-potential sensitive fluorescent probes were used to detect membrane tension induced changes in DOPC vesicles exposed to osmotic stress. Experiments confirmed that dipole potential of DOPC bilayer decreases at higher membrane tensions. These results are suggestive of a potentially new mechanosensing mechanism by which mechanically induced structural changes in the lipid bilayer membrane could modulate the function of membrane proteins by altering electrostatic interactions and energetics of protein conformational states. [Copyright &y& Elsevier]

Abstract: Evidence that membrane surface tension regulates water fluxes in intact cells of a Saccharomyces cerevisiae strain overexpressing aquaporin AQY1 was obtained by assessing the osmotic water transport parameters in cells equilibrated in different osmolarities. The osmotic water permeability coefficients (P f) obtained for yeast cells overexpressing AQY1 incubated in low osmolarity buffers were similar to those obtained for a double mutant aqy1aqy2 and approximately three times lower (with higher activation energy, E a) than values obtained for cells incubated in higher osmolarities (with lower E a). Moreover, the initial inner volumes attained a maximum value for cells equilibrated in lower osmolarities (below 0.75 M) suggesting a pre-swollen state with the membrane under tension, independent of aquaporin expression. In this situation, the impairment of water channel activity suggested by lower P f and higher E a could probably be the first available volume regulatory tool that, in cooperation with other osmosensitive solute transporters, aims to maintain cell volume. The results presented point to the regulation of yeast water channels by membrane tension, as previously described in other cell systems. [Copyright &y& Elsevier]

Abstract: The mechanosensitive channel of small conductance, MscS, is one of the most extensively studied MS channels to date. Past and present research involves the discovery of its physiological role as an emergency valve in prokaryotes up to detailed investigations of its conductive properties and gating mechanism. In this review, we summarize the findings on its structure and function obtained by experimental and theoretical approaches. A special focus is given to its pharmacology, since various compounds have been shown to affect the activity of this channel. These compounds have particularly been helpful for understanding the interaction of MscS with the lipid bilayer, as well as recognizing the potential of this channel as a target for novel types of antibiotics. [Copyright &y& Elsevier]

Abstract: I have previously proposed a possible role for electrostatic interactions in the dynamics of chromosome motions during prometaphase, metaphase, and anaphase in primitive eukaryotic cells. The present work focuses on a biophysical mechanism for breakdown and reassembly of the nuclear envelope based on electrostatics. Intracellular pH rises to a peak at mitosis, and decreases through cytokinesis. This result, in conjunction with an observed 50% elevation in the whole cell content of sialic acid preceding mitosis, could set the stage for a precisely timed increase in net negative nuclear envelope charge resulting from an observed release of from nuclear envelope stores just prior to nuclear envelope breakdown. The resulting increased electrostatic stress in these membranes could provide sufficient electrostatic energy for their breakdown. At late anaphase and early telophase, a decrease in the whole cell content of sialic acid is accompanied by a decline in intracellular pH. These changes would decrease the mutual electrostatic repulsion of membrane fragments, allowing membrane reassembly to occur for the nuclear envelopes of nascent daughter cells. [Copyright &y& Elsevier]

Very little is known about the molecular mechanisms supporting living cell membrane electropermeabilization. This concept is based on the local membrane permeability induced by cell exposure to brief and intense external electric field pulses. During the electric field application, an electro-induced membrane electric potential difference is created that is locally associated with the dielectric properties of the plasma membrane. When the new membrane electric potential difference locally reaches a critical value, a local alteration of the membrane structure is induced and leads to reversible permeabilization. In our study, we attempted to determine whether mechanical tension could modulate the triggering of membrane electropermeabilization. Change in lateral tension of Chinese Hamster Ovary cell membrane has been osmotically induced. Cell electropermeabilization was performed in the minute time range after the osmotic stress, i.e., before the regulatory volume decrease being activated by the cell. Living cell electropermeabilization was analyzed on cell population using flow cytometry. We observed that electropermeabilization triggering was significantly facilitated when the lateral membrane tension was increased. The main conclusion is that the critical value of transmembrane potential needed to trigger membrane electropermeabilization, is smaller when the membrane is under lateral mechanical constraint. This supports the hypothesis that both mechanical and electrical constraints play a key role in transient membrane destabilization. [Copyright &y& Elsevier]

This study represents an attempt to achieve a better understanding of the stomatocyte–echinocyte transition in the shape of red blood cells. We determined experimentally the index of cell shape at various ionic strengths and osmolarities for native and trypsin-treated human erythrocytes. For every given composition of the outer phase, we calculated the ionic strength in the cells and the transmembrane electric potential using a known theoretical model. Next, we described theoretically the electric double layers formed on both sides of the cell membrane, and derived expressions for the tensions of the two membrane leaflets. Taking into account that the cell-shape index depends on the tension difference between the two leaflets, we fitted the experimental data with the constructed physicochemical model. The model, which agrees well with the experiment, indicates that the tension difference between the two leaflets is governed by the different adsorptions of counterions at the two membrane surfaces, rather than by the direct contribution of the electric double layers to the membrane tension. Thus, with the rise of the ionic strength, the counterion adsorption increases stronger at the outer leaflet, whose stretching surface pressure becomes greater, and whose area expands relative to that of the inner leaflet. Hence, there is no contradiction between the bilayer-couple hypothesis and the electric double layer theory, if the latter is upgraded to account for the effect of counterion-adsorption on the membrane tension. The developed quantitative model can be applied to predict the shape index of cells upon a stomatocyte–discocyte–echinocyte transformation at varying composition of the outer medium. [Copyright &y& Elsevier]

Sculpting a flat patch of membrane into an endocytic vesicle requires curvature generation on the cell surface, which is the primary function of the endocytosis machinery. Using super-resolved live cell fluorescence imaging, we demonstrate that curvature generation by individual clathrin-coated pits can be detected in real time within cultured cells and tissues of developing organisms. Our analyses demonstrate that the footprint of clathrin coats increases monotonically during the formation of pits at different levels of plasma membrane tension. These findings are only compatible with models that predict curvature generation at the early stages of endocytic clathrin pit formation. We also found that CALM adaptors associated with clathrin plaques form clusters, whereas AP2 distribution is more homogenous. Considering the curvature sensing and driving roles of CALM, we propose that CALM clusters may increase the strain on clathrin lattices locally, eventually giving rise to rupture and subsequent pit completion at the edges of plaques. • Endocytic clathrin coats develop curvature starting from early stages of their formation • Formation of clathrin pits does not depend on a late-stage flat-to-curved transition • Membrane tension does not alter the mechanism of curvature generation by clathrin pits • CALM adaptors form distinct clusters beneath the clathrin plaques Clathrin-mediated endocytosis facilitates internalization of lipids and proteins from the cell surface and requires assembly of a curved clathrin coat. Using super-resolution live cell imaging, Willy et al. show that invagination of endocytic pits is synchronous with clathrin coat assembly and does not require transforming flat clathrin lattices into spheroids. [ABSTRACT FROM AUTHOR]

Organization of dynamic cellular structure is crucial for a variety of cellular functions. In this study, we report that Drosophila and Aedes have highly elastic cell membranes with extremely low membrane tension and high resistance to mechanical stress. In contrast to other eukaryotic cells, phospholipids are symmetrically distributed between the bilayer leaflets of the insect plasma membrane, where phospholipid scramblase (XKR) that disrupts the lipid asymmetry is constitutively active. We also demonstrate that XKR-facilitated phospholipid scrambling promotes the deformability of cell membranes by regulating both actin cortex dynamics and mechanical properties of the phospholipid bilayer. Moreover, XKR-mediated construction of elastic cell membranes is essential for hemocyte circulation in the Drosophila cardiovascular system. Deformation of mammalian cells is also enhanced by the expression of Aedes XKR, and thus phospholipid scrambling may contribute to formation of highly deformable cell membranes in a variety of living eukaryotic cells. [Display omitted] • Compared with mammalian cells, Drosophila cells have a highly elastic cell membrane • Drosophila XKR promotes membrane deformation by constitutive phospholipid scrambling • Phospholipid scrambling affects actin cortex dynamics and lipid bilayer mechanics • Deformability of mammalian cells can also be enhanced by phospholipid scrambling Shiomi et al. show that Drosophila cells possess a cell membrane with extreme deformability and resistance to mechanical stress, where constitutively active phospholipid scramblase XKR disturbs the asymmetric distribution of phospholipids and promotes the deformability of cell membranes by regulating both actin cortex dynamics and mechanical properties of the phospholipid bilayer. [ABSTRACT FROM AUTHOR]

During mitochondrial fission, key molecular and cellular factors assemble on the outer mitochondrial membrane, where they coordinate to generate constriction. Constriction sites can eventually divide or reverse upon disassembly of the machinery. However, a role for membrane tension in mitochondrial fission, although speculated, has remained undefined. We capture the dynamics of constricting mitochondria in mammalian cells using live-cell structured illumination microscopy (SIM). By analyzing the diameters of tubules that emerge from mitochondria and implementing a fluorescence lifetime-based mitochondrial membrane tension sensor, we discover that mitochondria are indeed under tension. Under perturbations that reduce mitochondrial tension, constrictions initiate at the same rate, but are less likely to divide. We propose a model based on our estimates of mitochondrial membrane tension and bending energy in living cells which accounts for the observed probability distribution for mitochondrial constrictions to divide. [Display omitted] • Mitochondria constricted by canonical fission factors do not invariably divide • The average tension for mitochondria that divide is higher than for those that do not • Depolymerizing microtubules or inhibiting myosin II reduces mitochondrial tension • Probability of division, but not of constriction, depends on mitochondrial tension Mahecic et al. show that mitochondria constricted by the fission machinery do not always divide. Constricted mitochondria that divide have increased membrane tension compared to those that relax to an unconstricted state. Mitochondrial tension, shown to depend upon microtubules and actomyosin contractility, increases the probability of division. [ABSTRACT FROM AUTHOR]

Corner-supported modular steel buildings (CMSBs) are mainly composed of repetitive room-sized modules and inter-module connections. However, there is a lack of relevant understanding on the structural performance of CMSBs such as lateral stiffness. This study therefore investigated the lateral stiffness of the two-storey planar modular structure taken from CMSBs with the vertical rotary inter-module connections. Three full-scale monotonic experiments representing container-type modules, framed modules and their combination, were carried out to evaluate their lateral performance. The results indicated that all the three structures showed the satisfactory ductile behavior but the container-type modular structure could possess much higher initial stiffness when subjected to lateral load. Two lateral-force resistance mechanisms with different structural configurations were clarified including the framed moment resisting mechanism and the membrane tension action mechanism. The load transferring mechanism of inter-module connections was analyzed where modules stiffness as well as inter-module connections rotational stiffness were considered. In this way, theoretical modellings were developed to estimate the initial lateral stiffness of such two-storey modular structures and verified by the experimental results. Furthermore, the bending moment transferred by inter-module connections was obtained from the theoretical derivation and used to demonstrate the above load transferring of inter-module connections. • Full-scale experiments on two-storey corner-supported modular steel structures with the rotary inter-module connections. • The lateral-force resistance mechanisms with different structural configurations. • The load transferring mechanism of inter-module connections. • Theoretical modellings to estimate the initial lateral stiffness of such two-storey modular structures. • The design recommendations of the inter-module connections. [ABSTRACT FROM AUTHOR]

In development, wound healing, and cancer metastasis, vertebrate cells move through 3D interstitial matrix, responding to chemical and physical guidance cues. Protrusion at the cell front has been extensively studied, but the retraction phase of the migration cycle is not well understood. Here, we show that fast-moving cells guided by matrix cues establish positive feedback control of rear retraction by sensing membrane tension. We reveal a mechanism of rear retraction in 3D matrix and durotaxis controlled by caveolae, which form in response to low membrane tension at the cell rear. Caveolae activate RhoA-ROCK1/PKN2 signaling via the RhoA guanidine nucleotide exchange factor (GEF) Ect2 to control local F-actin organization and contractility in this subcellular region and promote translocation of the cell rear. A positive feedback loop between cytoskeletal signaling and membrane tension leads to rapid retraction to complete the migration cycle in fast-moving cells, providing directional memory to drive persistent cell migration in complex matrices. • Fast-moving cells in 3D matrix establish low membrane tension at the rear • Caveolae form in response to low membrane tension and recruit the GEF Ect2 • Ect2 activates RhoA to promote F-actin organization and rear retraction • Positive feedback between membrane tension and contractility reinforces retraction Cell migration through 3D matrix is critical to developmental and disease processes, but the mechanisms that control rear retraction are poorly understood. Hetmanski et al. show that differential membrane tension allows caveolae to form at the rear of migrating cells and activate the contractile actin cytoskeleton to promote rapid retraction. [ABSTRACT FROM AUTHOR]

• The present study attempts to simulate cyto-membrance tension by means of surface elasticity theory. • The present study attempts to investigate the effect of cyto-membrance tension on ligand-receptor bond in the steady state. • The present study uses Green's function method to tackle the coupling between the stochasticity of ligand-receptor bond and elasticity of the bulk. This present study investigates the effect of membrane tension on the molecular-mediated adhesion between two soft elastic materials in a steady state, which simulates the specific adhesion between two cells with cyto-membrane tension taken into consideration. A coupled surface elasticity-bulk elasticity-stochastic model is developed to describe the adhesive contact scenario, which is represented by a Fredholm's equation of the second kind. The numerical results show that the rupture behavior of the two elastic materials transmits from Griffith-like mode to Bell's model when the adhesion size decreases. Unlike the classic case (Wang and Gao, 2010), the pull-off stress exhibits a non-monotonic dependence on the adhesion size ascribed to the presence of membrane tension. In addition, the interfacial stresses become evenly distributed attributed to membrane tension, which again verifies the conclusion that membrane tension facilitates adhesion optimization. [ABSTRACT FROM AUTHOR]

Summary Caveolae, flask-shaped pits covered by caveolin-cavin coats, are abundant features of the plasma membrane of many cells. Besides appearing as single-membrane indentations, caveolae are organized as superstructures in the form of rosette-like clusters, whose mechanism of assembly and biological functions have been elusive. Here, we propose that clustering of caveolae in mature muscle cells is driven by forces originating from the elastic energy of membrane-bending deformations and membrane tension. We substantiate this mechanism by computational modeling, which recovers the unique shapes observed for the most ubiquitous caveolar clusters. We support the agreement between the calculated and observed configurations by electron tomography of caveolar clusters. The model predicts the experimentally assessable dependence of caveolar clustering on membrane tension and on the degree of the caveolar coat assembly. We reveal a difference in conformation and, possibly, in function and formation mechanism between caveolar clusters of muscle cells and of adipocytes. Highlights • Caveolar superstructure formation can be driven by membrane curvature • Caveolar rosettes are stabilized by low and destabilized by high membrane tensions • Large rosettes can contribute to the mechano-protective function of caveolae • Configurations of caveolar rosettes of muscle cells differ from those of adipocytes Golani, Ariotti et al. propose a mechanism of caveolar cluster formation based on the elastic energy of membrane bending deformations and membrane tension. Using computational modeling, they reproduce the shapes of caveolar clusters in muscle cells observed by electron microscopy and predict assessable dependencies of caveolar clustering on membrane tension. [ABSTRACT FROM AUTHOR]