Transmission Of Mechanical Stresses Research Articles

Membrane tension induces F-actin reorganization and flow in a biomimetic model cortex

The accumulation and transmission of mechanical stresses in the cell cortex and membrane determines the mechanics of cell shape and coordinates essential physical behaviors, from cell polarization to cell migration. However, the extent that the membrane and cytoskeleton each contribute to the transmission of mechanical stresses to coordinate diverse behaviors is unclear. Here, we reconstitute a minimal model of the actomyosin cortex within liposomes that adheres, spreads and ultimately ruptures on a surface. During spreading, accumulated adhesion-induced (passive) stresses within the membrane drive changes in the spatial assembly of actin. By contrast, during rupture, accumulated myosin-induced (active) stresses within the cortex determine the rate of pore opening. Thus, in the same system, devoid of biochemical regulation, the membrane and cortex can each play a passive or active role in the generation and transmission of mechanical stress, and their relative roles drive diverse biomimetic physical behaviors.

Three-Dimensional Monolayer Stress Microscopy

Many biological processes involve the collective generation and transmission of mechanical stresses across cell monolayers. In these processes, the monolayer undergoes lateral deformation and bending because of the tangential and normal components of the cell-generated stresses. Monolayer stress microscopy (MSM) methods have been developed to measure the intracellular stress distribution in cell monolayers. However, current methods assume plane monolayer geometry and neglect the contribution of bending to the intracellular stresses. This work introduces a three-dimensional (3D) MSM method that calculates monolayer stress from measurements of the 3D traction stresses exerted by the cells on a flexible substrate. The calculation is carried out by imposing equilibrium of forces and moments in the monolayer, subject to external loads given by the 3D traction stresses. The equilibrium equations are solved numerically, and the algorithm is validated for synthetic loads with known analytical solutions. We present 3D-MSM measurements of monolayer stress in micropatterned islands of endothelial cells of different sizes and shapes. These data indicate that intracellular stresses caused by lateral deformation emerge collectively over long distances; they increase with the distance from the island edge until they reach a constant value that is independent of island size. On the other hand, bending-induced intracellular stresses are more concentrated spatially and remain confined to within one to two cell lengths of bending sites. The magnitude of these bending stresses is highest at the edges of the cell islands, where they can exceed the intracellular stresses caused by lateral deformations. Our data from nonpatterned monolayers suggests that biomechanical perturbations far away from monolayer edges also cause significant localized alterations in bending tension. The localized effect of bending-induced stresses may be important in processes like cellular extravasation, which are accompanied by significant normal deflections of a cell monolayer (i.e., the endothelium) and require localized changes in monolayer permeability.

Long-range correlations in the mechanics of small DNA circles under topological stress revealed by multi-scale simulation.

It is well established that gene regulation can be achieved through activator and repressor proteins that bind to DNA and switch particular genes on or off, and that complex metabolic networks determine the levels of transcription of a given gene at a given time. Using three complementary computational techniques to study the sequence-dependence of DNA denaturation within DNA minicircles, we have observed that whenever the ends of the DNA are constrained, information can be transferred over long distances directly by the transmission of mechanical stress through the DNA itself, without any requirement for external signalling factors. Our models combine atomistic molecular dynamics (MD) with coarse-grained simulations and statistical mechanical calculations to span three distinct spatial resolutions and timescale regimes. While they give a consensus view of the non-locality of sequence-dependent denaturation in highly bent and supercoiled DNA loops, each also reveals a unique aspect of long-range informational transfer that occurs as a result of restraining the DNA within the closed loop of the minicircles.

Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues.

Directed cell migration is a complex process that involves front-rear polarization, characterized by cell adhesion and cytoskeleton-based protrusion, retraction, and contraction of either a single cell or a cell collective. Single cell polarization depends on a variety of mechanochemical signals including external adhesive cues, substrate stiffness, and confinement. In cell ensembles, coordinated polarization of migrating tissues results not only from the application of traction forces on the extracellular matrix but also from the transmission of mechanical stress through intercellular junctions. We focus here on the impact of mechanical cues on the establishment and maintenance of front-rear polarization from single cell to collective cell behaviors through local or large-scale mechanisms.

Desmin Intermediate Filaments Form a Stress-Transmitting and Stress-Signaling Network In Muscle

INTRODUCTION: Muscle cells respond to stimuli such as stretch, exercise and electrical activation. Structurally, the cell’s desmin intermediate filament (IF) is strategically located between Z-disks to provide support and connections for intracellular organelles such as nuclei and mitochondria. However, the biological and/or mechanical significance of these interconnections are not clear. PURPOSE: The purpose of this study was to define the role of the desmin IF network in regulating nuclear strain, force transmission and mechanical stress-induced JNK signaling in muscle. METHODS: Plasmid DNA encoding a GFP-desmin (GFPDS) chimeric protein was introduced into desmin null (DSN) mouse muscle by electroporation. Muscles from wild type (WT, n=6) and either DSN (n=7), or transfected DSN muscles (n=9) were examined. Desmin’s biological role was probed by stretching isolated muscles and measuring Jun N-terminal kinase (JNK) phosphorylation. Force transmission was quantified by measuring isometric force generation after an eccentric contraction bout. Single fibers were imaged during deformation to quantify nuclear shape and strain. RESULTS: Nuclei in WT muscle subjected to stretch increased length/width ratio (i.e., aspect ratio with increased sarcomere length (1.25±.04 μm-1) while nuclei in DSN were significantly less deformed (0.268±.07 μm-1). Nuclear deformation pattern in DSN muscles transfected with GFPDS showed restored shape and deformation (1.22±.06 μm-1). WT muscle subjected to an eccentric contraction protocol demonstrated significantly more stress decrease (69±10%Po) compared to DSN muscles (37±4%Po) but this change within DSN muscles transfected with GFPDS was rescued to near WT levels (57±9 %Po). Finally, while stretch of WT muscle strongly phosphorylated both the 54 kDa and 46 kDa isoforms of JNK, DSN muscle showed a near absence of stretch-induced signaling to JNK. This signaling was partially rescued in DSN muscles transfected with GFPDS. DISCUSSION: These experiments clearly demonstrate that desmin IFs are involved in mechanical stress transmission, nuclear deformation and signaling. This demonstration of biomechanical integration by the desmin IF system suggests that it plays an active biological role in muscle in addition to its accepted structural role.

Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues

Epithelial-mesenchymal transition (EMT) is a phenotypic shift wherein epithelial cells lose or loosen attachments to their neighbors and assume a mesenchymal-like morphology. EMT drives a variety of developmental processes, but may also be adopted by tumor cells during neoplastic progression. EMT is regulated by both biochemical and physical signals from the microenvironment, including mechanical stress, which is increasingly recognized to play a major role in development and disease progression. Biological systems generate, transmit and concentrate mechanical stress into spatial patterns; these gradients in mechanical stress may serve to spatially pattern developmental and pathologic EMTs. Here we review how epithelial tissues generate and respond to mechanical stress gradients, and highlight the mechanisms by which mechanical stress regulates and patterns EMT.

Quantification of in Vivo Left Ventricular Torsion and Principal Strains in Mouse Models of Hypertrophic and Dilated Cardiomyopathy

The deformations and twisting of the left ventricular (LV) wall, quantified by strain and torsion, provide insight into its regional and global contractile function. In this study, we investigated the influence of proteins entailing myocyte contractility and structural stability on ventricular biomechanics using mouse models with alterations in contractile proteins. The pattern and timing of LV strain and torsion in 2∼3 month mice that lack cardiac myosin binding protein-C (cMyBP-C-/-, n=6, cMyBP-C+/-, n=6), a thick filament-associated sarcomeric protein, and muscle LIM protein (MLP-/-, n=6), a cytoskeleton protein that is thought to be involved in transmission of mechanical stress, were evaluated against wild-type mice (n=6) in vivo using magnetic resonance imaging. Both cMyBP-C-/- and MLP-/- mice exhibited a severe depression in systolic function as indicated by decreased LV ejection fractions compared to wild-type mice. A significant reduction in LV torsion and principal strains E1 and E2, associated with radial wall thickening and circumferential shortening, respectively, were observed in cMyBP-C -/- and MLP-/- mice. Interestingly, reductions in LV torsion were also observed in heterozygous cMyBP-C null mice (cMyBP-C+/-). The time course of peak fiber torsion and strain appeared to be accelerated in cMyBP-C-/- mice, while peak strain development was slowed in MLP-/- mice. The lack of MyBP-C and MLP in the cardiac myocyte led to hypertrophic and dilated cardiomyopathy, respectively, and resulted in severe deficits in the overall contractile function of the heart. However, the pattern and time course of LV torsion and principal strain development appear to differ in these two models of heart failure, reflecting a contrast in the functional roles of cMyBP-C and MLP in the myocyte.

Stress transmission within the cell.

An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. During past decades, it has become evident that the deformable cytoskeleton (CSK), an intracellular network of various filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical responses. To understand how mechanical forces regulate cellular functions, it is necessary to first understand how the CSK develops mechanical stresses in response to applied forces, and how those stresses are propagated through the CSK where various signaling molecules are immobilized. New experimental techniques have been developed to quantify cytoskeletal mechanics, which together with new computational approaches have given rise to new theories and models for describing mechanics of living cells. In this article, we discuss current understanding of cell biomechanics by focusing on the biophysical mechanisms that are responsible for the development and transmission of mechanical stresses in the cell and their effect on cellular functions. We compare and contrast various theories and models of cytoskeletal mechanics, emphasizing common mechanisms that those theories are built upon, while not ignoring irreconcilable differences. We highlight most recent advances in the understanding of mechanotransduction in the cytoplasm of living cells and the central role of the cytoskeletal prestress in propagating mechanical forces along the cytoskeletal filaments to activate cytoplasmic enzymes. It is anticipated that advances in cell mechanics will help developing novel therapeutics to treat pulmonary diseases like asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Prediction of adjacent vertebral fracture risk associated with vertebroplasty — A computer-based simulation study

Vertebrplasty involved injecting cement into a fractured vertebra to provide stabilisation. There is clinical evidence to suggest however that vertebroplasty may be assocated with a higher risk of adjacent vertebral fracture; which may be due to the change in material properties of the post-procedure vertebra modifying the transmission of mechanical stresses to adjacent vertebrae.

Transmission of Mechanical Stresses within the Cytoskeleton of Adherent Cells: A Theoretical Analysis Based on a Multi-Component Cell Model

How environmental mechanical forces affect cellular functions is a central problem in cell biology. Theoretical models of cellular biomechanics provide relevant tools for understanding how the contributions of deformable intracellular components and specific adhesion conditions at the cell interface are integrated for determining the overall balance of mechanical forces within the cell. We investigate here the spatial distributions of intracellular stresses when adherent cells are probed by magnetic twisting cytometry. The influence of the cell nucleus stiffness on the simulated nonlinear torque-bead rotation response is analyzed by considering a finite element multi-component cell model in which the cell and its nucleus are considered as different hyperelastic materials. We additionally take into account the mechanical properties of the basal cell cortex, which can be affected by the interaction of the basal cell membrane with the extracellular substrate. In agreement with data obtained on epithelial cells, the simulated behaviour of the cell model relates the hyperelastic response observed at the entire cell scale to the distribution of stresses and strains within the nucleus and the cytoskeleton, up to cell adhesion areas. These results, which indicate how mechanical forces are transmitted at distant points through the cytoskeleton, are compared to recent data imaging the highly localized distribution of intracellular stresses.