Mechanotransduction down to individual actin filaments

The actin cytoskeleton plays an essential role in a cell's ability to generate and sense forces, both internally and in interaction with the outside world. The transduction of mechanical cues into biochemical reactions in cells, in particular, is a multi-scale process which requires a variety of approaches to be understood. This review focuses on understanding how mechanical stress applied to an actin filament can affect its assembly dynamics. Today, experiments addressing this issue at the scale of individual actin filaments are emerging and bring novel insight into mechanotransduction. For instance, recent data show that actin filaments can act as mechanosensors, as an applied tension or curvature alters their conformation and their affinity for regulatory proteins. Filaments can also transmit mechanical tension to other proteins, which consequently change the way they interact with the filaments to regulate their assembly. These results provide evidence for mechanotransduction at the scale of individual filaments, showing that forces participate in the regulation of filament assembly and organization. They bring insight into the elementary events coupling mechanics and biochemistry in cells. The experiments presented here are linked to recent technical developments, and certainly announce the advent of more exciting results in the future.     

Effects of milking frequency on lying down and getting up behaviour in dairy cows

The objective of this study was to investigate if cows milked twice per day have more difficulty lying down and getting up and spend less time lying than cows milked three times per day. Seventeen cows of the Swedish Red and White Cattle Breed were studied, seven of which were milked twice daily (2M) and ten were milked three times (3M) daily. They were kept in individual cubicles, that were closed in the rear end with a rope. They had free access to a mixture of silage, hay and concentrate. The individual cows were video-recorded for 24h every fourth week, starting four weeks after calving for four times. The 2M cows stood significantly longer, 128.11min, than the 3M cows, 64.88min, (P<0.01) during the 4h before morning milking. The 2M cows also had a tendency for longer duration of standing rumination (P=0.059) as well as significantly more bouts of standing rumination (P<0.01) during these hours than the 3M cows. The cows in the 3M group spent less time on the getting up movement (P<0.05) during the 4h before morning milking. The distribution of the lying bouts during these 4h differed significantly between the groups, where the 3M cows had fewer lying bouts shorter than 15min and more lying bouts longer than 90min. The results indicate that milking three times a day contributes to increased comfort in high-producing dairy cows.     

Mechanotransduction and fibrosis

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.     

Mechanotransduction in adipocytes

Obesity is widely recognized as a major public health problem due to its strong association with a number of serious chronic diseases including hyperlipidemia, hypertension, type II diabetes and coronary atherosclerotic heart disease. During the development of obesity, the positive energy balance involves recruitment of new adipocytes from preadipocytes in adipose tissue, which have proliferated and differentiated. Given that cells in adipose tissues are physiologically exposed to compound mechanical loading: tensile, compressive and shear strains/stresses, which are caused by bodyweight loads as well as by weight-bearing, it is important to determine whether the adipose conversion process is influenced by mechanical stimulations. In this article we provide a comprehensive review of the experimental studies addressing mechanotransduction in adipocytes, as well as of mathematical and computational models that are useful for studying mechanotransduction in adipocytes or for quantifying the responsiveness of adipocytes to different types of mechanical loading. The new understanding that adipogenesis is influenced by mechanical stimulations has the potential to open new and important research paths, driven by mechanotransduction, to explore mechanisms as well as treatment approaches in obesity and related conditions.     

Mechanotransduction in cells

Cell-matrix and cell-cell adhesions critically influence cell metabolism, protein synthesis, cell survival, cytoskeletal architecture and consequently cell mechanical properties such as migration, spreading and contraction. An important group of adhesive transmembrane receptors that mechanically link the ECM (extracellular matrix) with the internal cytoskeleton are integrins which are intimately connected with the FAs (focal adhesions) which consists of many proteins. The transient formation of FAs is greatly augmented either through externally applied tension to the cell or internally through myosin II-driven cell contractility. Exactly which protein(s) within FAs sense, transmit and respond to mechanical stress is currently debated and numerous candidates have been proposed.     

Mechanotransduction in leukocyte activation: a review

We review recent evidence which suggests that leukocytes in the circulation and in the tissue may readily respond to physiological levels of fluid shear stress in the range between about 1 and 10 dyn/cm 2, a range that is below the level to achieve a significant passive, viscoelastic response. The response of activated neutrophilic leukocytes to fluid shear consists of a rapid retraction of lamellipodia with membrane detachment from integrin binding sites. In contrast, a subgroup of non-activated neutrophils may project pseudopods after exposure to fluid shear stress. The evidence suggests that G-protein coupled receptor downregulation by fluid shear with concomitant downregulation of Rac-related small GTPases and depolymerization of F-actin serves to retract the lamellipodia in conjunction with proteolytic cleavage of beta 2 integrin to facilitate membrane detachment. Furthermore, there exists a mechanism to up- and down-regulate the fluid shear-response, which involves nitric oxide and the second messenger cyclic guanosine monophosphate (cGMP). Many physiological activities of circulating leukocytes are under the influence of fluid shear stress, including transendothelial migration of lymphocytes. We describe a disease model with chronic hypertension that suffers from an attenuated fluid shear-response with far reaching implications for microvascular blood flow.     

Mechanotransduction in Caenorhabditis elegans

One of the looming mysteries in signal transduction today is the question of how mechanical signals, such as pressure or mechanical force delivered to a cell, are interpreted to direct biological responses. All living organisms, and probably all cells, have the ability to sense and respond to mechanical stimuli. At the single-cell level, mechanical signaling underlies cell-volume control and specialized responses such as the prevention of poly-spermy in fertilization. At the level of the whole organism, mechanotransduction underlies processes as diverse as stretch-activated reflexes in vascular epithelium and smooth muscle; gravitaxis and turgor control in plants; tissue development and morphogenesis; and the senses of touch, hearing, and balance. Intense genetic, molecular, and elecrophysiological studies in organisms ranging from nematodes to mammals have highlighted members of the recently discovered DEG/ENaC family of ion channels as strong candidates for the elusive metazoan mechanotransducer. Here, we discuss the evidence that links DEG/ENaC ion channels to mechanotransduction and review the function of Caenorhabiditis elegans members of this family called degenerins and their role in mediating mechanosensitive behaviors in the worm.     

Mechanotransduction through the cytoskeleton

We constructed a model cytoskeleton to investigate the proposal that this interconnected filamentous structure can act as a mechano- and signal transducer. The model cytoskeleton is composed of rigid rods representing actin filaments, which are connected with springs representing cross-linker molecules. The entire mesh is placed in viscous cytoplasm. The model eukaryotic cell is submitted to either shock wave-like or periodic mechanical perturbations at its membrane. We calculated the efficiency of this network to transmit energy to the nuclear wall as a function of cross-linker stiffness, cytoplasmic viscosity, and external stimulation frequency. We found that the cytoskeleton behaves as a tunable band filter: for given linker molecules, energy transmission peaks in a narrow range of stimulation frequencies. Most of the normal modes of the network are spread over the same frequency range. Outside this range, signals are practically unable to reach their destination. Changing the cellular ratios of linker molecules with different elastic characteristics can control the allowable frequency range and, with it, the efficiency of mechanotransduction.     

Mechanotransduction at cadherin-mediated adhesions

Cell-to-cell junctions are crucial mechanical and signaling hubs that connect cells within tissues and probe the mechanics of the surrounding environment. Although the capacity of cell-to-extracellular-matrix (ECM) adhesions to sense matrix mechanics and proportionally modify cell functions is well established, cell-cell adhesions only recently emerged as a new class of force sensors. This finding exposes new pathways through which force can instruct cell functions. This review highlights recent findings, which demonstrate that protein complexes associated with classical cadherins, the principal architectural proteins at cell-cell junctions in all soft tissues, are mechanosensors. We further discuss the current understanding of the rudiments of a cadherin-based mechanosensing and transduction pathway, which is distinct from the force sensing machinery of cell-ECM adhesions.     

Mechanotransduction and focal adhesions

Cellular FAs (focal adhesions) respond to internal and external mechanical stresses which make them prime candidates for mechanotransduction. Recent observations showed that the FA proteins including vinculin, FAK (FA kinase) and p130Cas are crucial for the ability of cells to transmit forces and to generate cytoskeletal tension. When mechanically stimulated, cells respond by modulating the spreading area, remodel the actin cytoskeleton, activate actomyosin interactions, recruit integrins and reinforce FAs and cytoskeletal structures. These complex cellular responses are orchestrated such that mechanical stresses within the FA complex remained within a narrow range.     

Mechanotransduction in intervertebral discs

Mechanotransduction plays a critical role in intracellular functioning—it allows cells to translate external physical forces into internal biochemical activities, thereby affecting processes ranging from proliferation and apoptosis to gene expression and protein synthesis in a complex web of interactions and reactions. Accordingly, aberrant mechanotransduction can either lead to, or be a result of, a variety of diseases or degenerative states. In this review, we provide an overview of mechanotransduction in the context of intervertebral discs, with a focus on the latest methods of investigating mechanotransduction and the most recent findings regarding the means and effects of mechanotransduction in healthy and degenerative discs. We also provide some discussion of potential directions for future research and treatments.     

Lung Ischemia: A Model for Endothelial Mechanotransduction

Endothelial cells in vivo are constantly exposed to shear associated with blood flow and altered shear stress elicits cellular responses (mechanotransduction). This review describes the role of shear sensors and signal transducers in these events. The major focus is the response to removal of shear as occurs when blood flow is compromised (i.e., ischemia). Pulmonary ischemia studied with the isolated murine lung or flow adapted pulmonary microvascular endothelial cells in vitro results in endothelial generation of reactive oxygen species (ROS) and NO. The response requires caveolae and is initiated by endothelial cell depolarization via K_ATP channel closure followed by activation of NADPH oxidase (NOX2) and NO synthase (eNOS), signaling through MAP kinases, and endothelial cell proliferation. These physiological mediators can promote vasodilation and angiogenesis as compensation for decreased tissue perfusion.     

Mechanotransduction in blood cells

Blood cells are subjected to various mechanical forces; including pressure, flow, shear force, gravity, and forces acting against them with varying stiffness (eg. blood vessel wall). Scientists have discovered that these forces have profound effects on cellular growth, differentiation, secretion of cytokines, cell death, and migration. These processes are called mechanotransduction, a conversion of mechanical forces to biochemical signals. In this article the author reviews biophysical forces that affect biological functions of blood cells and their responses in normal physiology and pathophysiology. Although input (forces) and output (cellular responses) have been well studied by utilizing recently developed various force-generating devices, the molecular mechanism of mechanotransudction is still a mystery. This is because reconstructing molecular interaction in the presence of mechanical forces in vitro is highly challenging and until now the molecular dynamics involved in structural changes caused by these forces are largely unknown. Nevertheless, the author has reviewed a few examples of potential structural effects on the molecular mechanism of mechanotransduction.