Universal physical responses to stretch in the living cell (original) (raw)
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Universal physical responses to stretch in the living
Nature, 2007
With every beat of the heart, inflation of the lung or peristalsis of the gut, cell types of diverse function are subjected to substantial stretch. Stretch is a potent stimulus for growth, differentiation, migration, remodelling and gene expression 1,2 . Here, we report that in response to transient stretch the cytoskeleton fluidizes in such a way as to define a universal response class. This finding implicates mechanisms mediated not only by specific signalling intermediates, as is usually assumed, but also by non-specific actions of a slowly evolving network of physical forces. These results support the idea that the cell interior is at once a crowded chemical space 3 and a fragile soft material in which the effects of biochemistry, molecular crowding and physical forces are complex and inseparable, yet conspire nonetheless to yield remarkably simple phenomenological laws. These laws seem to be both universal and primitive, and thus comprise a striking intersection between the worlds of cell biology and soft matter physics.
Combining Dynamic Stretch and Tunable Stiffness to Probe Cell Mechanobiology In Vitro
PLoS ONE, 2011
Cells have the ability to actively sense their mechanical environment and respond to both substrate stiffness and stretch by altering their adhesion, proliferation, locomotion, morphology, and synthetic profile. In order to elucidate the interrelated effects of different mechanical stimuli on cell phenotype in vitro, we have developed a method for culturing mammalian cells in a two-dimensional environment at a wide range of combined levels of substrate stiffness and dynamic stretch. Polyacrylamide gels were covalently bonded to flexible silicone culture plates and coated with monomeric collagen for cell adhesion. Substrate stiffness was adjusted from relatively soft (G9 = 0.3 kPa) to stiff (G9 = 50 kPa) by altering the ratio of acrylamide to bis-acrylamide, and the silicone membranes were stretched over circular loading posts by applying vacuum pressure to impart near-uniform stretch, as confirmed by strain field analysis. As a demonstration of the system, porcine aortic valve interstitial cells (VIC) and human mesenchymal stem cells (hMSC) were plated on soft and stiff substrates either statically cultured or exposed to 10% equibiaxial or pure uniaxial stretch at 1Hz for 6 hours. In all cases, cell attachment and cell viability were high. On soft substrates, VICs cultured statically exhibit a small rounded morphology, significantly smaller than on stiff substrates (p,0.05). Following equibiaxial cyclic stretch, VICs spread to the extent of cells cultured on stiff substrates, but did not reorient in response to uniaxial stretch to the extent of cells stretched on stiff substrates. hMSCs exhibited a less pronounced response than VICs, likely due to a lower stiffness threshold for spreading on static gels. These preliminary data demonstrate that inhibition of spreading due to a lack of matrix stiffness surrounding a cell may be overcome by externally applied stretch suggesting similar mechanotransduction mechanisms for sensing stiffness and stretch.
Mechanical behavior in living cells consistent with the tensegrity model
Proceedings of the National Academy of Sciences, 2001
Alternative models of cell mechanics depict the living cell as a simple mechanical continuum, porous filament gel, tensed cortical membrane, or tensegrity network that maintains a stabilizing prestress through incorporation of discrete structural elements that bear compression. Real-time microscopic analysis of cells containing GFP-labeled microtubules and associated mitochondria revealed that living cells behave like discrete structures composed of an interconnected network of actin microfilaments and microtubules when mechanical stresses are applied to cell surface integrin receptors. Quantitation of cell tractional forces and cellular prestress by using traction force microscopy confirmed that microtubules bear compression and are responsible for a significant portion of the cytoskeletal prestress that determines cell shape stability under conditions in which myosin light chain phosphorylation and intracellular calcium remained unchanged. Quantitative measurements of both static ...
A mechano-osmotic feedback couples cell volume to the rate of cell deformation
2021
Mechanics has been a central focus of physical biology in the past decade. In comparison, the osmotic and electric properties of cells are less understood. Here we show that a parameter central to both the physics and the physiology of the cell, its volume, depends on a mechano-osmotic coupling. We found that cells change their volume depending on the rate at which they change shape, when they spread, migrate or are externally deformed. Cells undergo slow deformation at constant volume, while fast deformation leads to volume loss. We propose a mechano-sensitive pump and leak model to explain this phenomenon. Our model and experiments suggest that volume modulation depends on the state of the actin cortex and the coupling of ion fluxes to membrane tension. This mechano-osmotic coupling defines a membrane tension homeostasis module constantly at work in cells, causing volume fluctuations associated with fast cell shape changes, with potential consequences on cellular physiology.
Active Prestress Leads to an Apparent Stiffening of Cells through Geometrical Effects
Biophysical Journal
Tuning of active prestress e.g. through activity of molecular motors constitutes a powerful cellular tool to adjust cellular stiffness through nonlinear material properties. Understanding this tool is an important prerequisite for our comprehension of cellular force response, cell shape dynamics and tissue organisation. Experimental data obtained from cell-mechanical measurements often show a simple linear dependence between mechanical prestress and measured differential elastic moduli. While these experimental findings could point to stress-induced structural changes in the material, we propose here a surprisingly simple alternative explanation in a theoretical study. We show how geometrical effects can give rise to increased cellular force response of cells in the presence of active prestress. The associated effective stress-stiffening is disconnected from actual stress-induced changes of the elastic modulus and should therefore be regarded as an apparent stiffening of the material. We argue that new approaches in experimental design are necessary to separate this apparent stress-stiffening due to geometrical effects from actual nonlinearities of the elastic modulus in prestressed cellular material.
Contractile Equilibration of Single Cells to Step Changes in Extracellular Stiffness
Biophysical Journal, 2012
Extracellular stiffness has been shown to alter long timescale cell behaviors such as growth and differentiation, but the cellular response to changes in stiffness on short timescales is poorly understood. By studying the contractile response of cells to dynamic stiffness conditions using an atomic force microscope, we observe a seconds-timescale response to a step change in extracellular stiffness. Specifically, we observe acceleration in contraction velocity (mm/min) and force rate (nN/min) upon a step decrease in stiffness and deceleration upon a step increase in stiffness. Interestingly, this seconds-timescale response to a change in extracellular stiffness is not altered by inhibiting focal adhesion signaling or stretch-activated ion channels and is independent of cell height and contraction force. Rather, the response timescale is altered only by disrupting cytoskeletal mechanics and is well described by a simple mechanical model of a constant velocity actuator pulling against an internal cellular viscoelastic network. Consistent with the predictions of this model, we find that an osmotically expanding hydrogel responds to step changes in extracellular stiffness in a similar manner to cells. We therefore propose that an initial event in stiffness sensing is establishment of a mechanical equilibrium that balances contraction of the viscoelastic cytoskeleton with deformation of the extracellular matrix.
Time scale and other invariants of integrative mechanical behavior in living cells
Physical review. E, Statistical, nonlinear, and soft matter physics, 2003
In dealing with systems as complex as the cytoskeleton, we need organizing principles or, short of that, an empirical framework into which these systems fit. We report here unexpected invariants of cytoskeletal behavior that comprise such an empirical framework. We measured elastic and frictional moduli of a variety of cell types over a wide range of time scales and using a variety of biological interventions. In all instances elastic stresses dominated at frequencies below 300 Hz, increased only weakly with frequency, and followed a power law; no characteristic time scale was evident. Frictional stresses paralleled the elastic behavior at frequencies below 10 Hz but approached a Newtonian viscous behavior at higher frequencies. Surprisingly, all data could be collapsed onto master curves, the existence of which implies that elastic and frictional stresses share a common underlying mechanism. Taken together, these findings define an unanticipated integrative framework for studying p...
Biophysical Journal, 2010
Cell spreading and attachment are integral to multiple physiological processes including wound healing, immune cell-antigen recognition, and tumor cell metastasis. We have discovered that Swiss 3T3 fibroblasts and CHO cells undergo periodic oscillations of the cell body during cell spreading that last from .5 hours after attachment to 1.5 hours and longer. The amplitude and duration of the oscillating phenotype are increased when microtubules are depolymerized. Previously we developed a mechanochemical ODE model describing a possible negative feedback from actomyosin based contractility to stretchactivated calcium channels in propagating cell oscillations. Cortical oscillations provide an ideal model for studying cytoskeleton regulation because the oscillation mechanism is easily quantifiable through the relative phase, amplitude, and period of native oscillations vs. those that have experienced perturbations. Further, we examine the spatiotemporal distribution of [Ca 2รพ i ] during cell oscillations. We propose that the interplay of the calcium and Rho A pathways both contribute to the propagation of cortical oscillations, with high levels of active Rho A replacing the need for highly dynamic calcium signaling.
Double power-law viscoelastic relaxation of living cells encodes motility trends
Scientific Reports, 2020
Living cells are constantly exchanging momentum with their surroundings. So far, there is no consensus regarding how cells respond to such external stimuli, although it reveals much about their internal structures, motility as well as the emergence of disorders. Here, we report that twelve cell lines, ranging from healthy fibroblasts to cancer cells, hold a ubiquitous double power-law viscoelastic relaxation compatible with the fractional Kelvin-Voigt viscoelastic model. Atomic Force Microscopy measurements in time domain were employed to determine the mechanical parameters, namely, the fast and slow relaxation exponents, the crossover timescale between power law regimes, and the cell stiffness. These cell-dependent quantities show strong correlation with their collective migration and invasiveness properties. Beyond that, the crossover timescale sets the fastest timescale for cells to perform their biological functions.