scholarly journals Spatiotemporal model of cellular mechanotransduction via Rho and YAP

2021 ◽  
Author(s):  
Javor K Novev ◽  
Mathias L Heltberg ◽  
Mogens H Jensen ◽  
Amin Doostmohammadi
Keyword(s):  
Mechanical Stimulus ◽  
Cell Polarization ◽  
Mechanical Stimuli ◽  
Spatiotemporal Model ◽  
Cyclic Stretching ◽  
Sustained Oscillations ◽  
Cellular Mechanotransduction ◽  
Sense And Respond ◽  
Open Question ◽  
Cell Force

Abstract How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio’s time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.

scholarly journals Spatiotemporal model of cellular mechanotransduction via Rho and YAP

2020 ◽  
Author(s):  
Javor K. Novev ◽  
Mathias L. Heltberg ◽  
Mogens H. Jensen ◽  
Amin Doostmohammadi
Keyword(s):  
Mechanical Stimulus ◽  
Cell Polarization ◽  
Mechanical Stimuli ◽  
Spatiotemporal Model ◽  
Cyclic Stretching ◽  
Sustained Oscillations ◽  
Cellular Mechanotransduction ◽  
Sense And Respond ◽  
Open Question ◽  
Cell Force

AbstractHow cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization.For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio’s time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.

scholarly journals Mechanotransduction in the Cardiovascular System: From Developmental Origins to Homeostasis and Pathology

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1607 ◽  
Author(s):  
Gloria Garoffolo ◽  
Maurizio Pesce
Keyword(s):  
Cardiovascular System ◽  
Mechanical Forces ◽  
Mechanical Stimuli ◽  
Flow Shear ◽  
Surrounding Matrix ◽  
Cellular Mechanotransduction ◽  
Flow Shear Stress ◽  
Sense And Respond ◽  
Metabolic Dysfunctions

With the term ‘mechanotransduction’, it is intended the ability of cells to sense and respond to mechanical forces by activating intracellular signal transduction pathways and the relative phenotypic adaptation. While a known role of mechanical stimuli has been acknowledged for developmental biology processes and morphogenesis in various organs, the response of cells to mechanical cues is now also emerging as a major pathophysiology determinant. Cells of the cardiovascular system are typically exposed to a variety of mechanical stimuli ranging from compression to strain and flow (shear) stress. In addition, these cells can also translate subtle changes in biophysical characteristics of the surrounding matrix, such as the stiffness, into intracellular activation cascades with consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes. Since cellular mechanotransduction has a potential readout on long-lasting modifications of the chromatin, exposure of the cells to mechanically altered environments may have similar persisting consequences to those of metabolic dysfunctions or chronic inflammation. In the present review, we highlight the roles of mechanical forces on the control of cardiovascular formation during embryogenesis, and in the development and pathogenesis of the cardiovascular system.

scholarly journals Unforgettable force – crosstalk and memory of mechanosensitive structures

2019 ◽  
Vol 400 (6) ◽  
pp. 687-698 ◽  
Author(s):  
Verena Kanoldt ◽  
Lisa Fischer ◽  
Carsten Grashoff
Keyword(s):  
Current Understanding ◽  
Muscular Dystrophies ◽  
Mechanical Stimuli ◽  
Cellular Mechanotransduction ◽  
Cardiovascular Defects ◽  
Mechanical Information ◽  
Sense And Respond ◽  
Mechanical Memory

Abstract The ability of cells to sense and respond to mechanical stimuli is crucial for many developmental and homeostatic processes, while mechanical dysfunction of cells has been associated with numerous pathologies including muscular dystrophies, cardiovascular defects and epithelial disorders. Yet, how cells detect and process mechanical information is still largely unclear. In this review, we outline major mechanisms underlying cellular mechanotransduction and we summarize the current understanding of how cells integrate information from distinct mechanosensitive structures to mediate complex mechanoresponses. We also discuss the concept of mechanical memory and describe how cells store information on previous mechanical events for different periods of time.

The initiation of nerve impulses by mesenteric Pacinian corpuscles

1950 ◽  
Vol 137 (886) ◽  
pp. 96-114 ◽  
Keyword(s):  
Conditioning Stimulus ◽  
Mechanical Stimulus ◽  
Constant Current ◽  
Mechanical Stimuli ◽  
Pacinian Corpuscles ◽  
Nerve Impulses ◽  
A Value ◽  
Test Shock ◽  
Long Duration ◽  
Refractory State

A preparation of a single Pacinian corpuscle in the cat’s mesentery has been used to study the initiation of nerve impulses in sensory endings. The minimum movement of a mechanical stimulator required to excite a single corpuscle has been found to be 0⋅5 μ in 100 μ sec. It has been difficult to produce repetitive discharges with rectangular pulses of long duration, either mechanical or of constant current. The latency between a mechanical stimulus and the initiation of an impulse has a value around 1⋅5 msec, for threshold stimuli, and this decreases to a minimum value around 0⋅5 msec, as the stimulus is increased; it is altered only slightly, if at all, by changes in the duration of the maintained displacement of the mechanical stimulator. Subthreshold mechanical stimuli have been shown to facilitate stimulation by electrical test shocks. The return of excitability at the ending is independent of the nature of the conditioning stimulus and varies but little with the nature of the test shock. The value of the latency at threshold is unaffected by the relatively refractory state. The relations of these results to various hypotheses are discussed, and it is suggested that these results can all be accounted for in terms of the known properties of axons.

Rapid Contractions and Associated Potentials in a Sand-Dwelling Anemone

1969 ◽  
Vol 51 (2) ◽  
pp. 513-528
Author(s):  
PETER E. PICKENS
Keyword(s):  
Maximum Size ◽  
Mechanical Stimulus ◽  
Retractor Muscle ◽  
Mechanical Stimuli ◽  
Nerve Impulses ◽  
Electrical Potentials ◽  
Spread Of Excitation ◽  
Electrical Stimuli ◽  
Withdrawal Response ◽  
Muscle Potential

1. Two kinds of electrical potentials can be recorded from the surface of the. retractor muscle of the anemone, Calamactis, during rapid contraction. These are large muscle action potentials and smaller pulses which are thought to be nerve spikes The latter resemble nerve impulses of higher organisms in that they are all-or-none and of short duration. 2. A nerve spike follows each of a pair of electrical stimuli, but the muscle potential and contraction occur only after the second shock, indicating that facilitation is required at the neuromuscular junction. 3. The size of the muscle potential and of the contraction are correlated with the interval between paired electrical stimuli. Maximum size is reached when stimuli are zoo msec. apart even though the minimum effective interval is 30 msec. 4. A muscle potential precedes contraction only along the upper part of the retractor muscle and this is the part that contracts rapidly during the withdrawal response. The lower retractor does not contract. 5. Conduction velocity along the upper retractor is higher than along the lower. The histological correlate of rapid conduction is a nerve net with large, long, longitudinally oriented fibres. 6. The refractory period of the conducting system of the upper retractor is shorter than that of the lower retractor. Consequently, spread of excitation toward the aboral end is limited if paired stimuli are further apart than 250-300 msec. 7. A mechanical stimulus which is just strong enough to elicit a withdrawal response evokes a single muscle potential of maximum size, suggesting that two nerve impulses closer together than 200 msec. precede the muscle potential. Stronger mechanical stimuli evoke a burst of muscle potentials.

scholarly journals Mechanosensitive calcium signaling promotes epithelial tight junction remodeling by activating RhoA

2021 ◽  
Author(s):  
Saranyaraajan Varadarajan ◽  
Rachel E. Stephenson ◽  
Eileen R. Misterovich ◽  
Jessica L. Wu ◽  
Ivan S. Erofeev ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intracellular Calcium ◽  
Tight Junctions ◽  
Calcium Influx ◽  
Cell Junctions ◽  
Mechanical Stimuli ◽  
Local Repair ◽  
Transient Activation ◽  
Epithelial Tight Junction ◽  
Sense And Respond

Epithelia maintain an effective barrier by remodeling cell-cell junctions in response to mechanical stimuli. Cells often respond to mechanical stress through activating RhoA and remodeling actomyosin. Previously, we found that local leaks in the barrier are rapidly repaired by localized, transient activation of RhoA – ″Rho flares″ – but how Rho flares are initiated remains unknown. Here, we discovered that intracellular calcium flashes occur in Xenopus laevis epithelial cells undergoing Rho flare-mediated remodeling of tight junctions. Calcium flashes originate at the site of barrier leaks and propagate into the cell. Depletion of intracellular calcium or inhibition of mechanosensitive calcium channels (MSC) reduced the amplitude of calcium flashes and diminished the activation of Rho flares. Furthermore, MSC-dependent calcium influx was necessary to maintain global barrier function by regulating local repair of tight junctions through efficient junction contraction. We propose that MSC-dependent calcium flashes are an important mechanism allowing epithelial cells to sense and respond to local leaks induced by mechanical stimuli.

scholarly journals The E. coli transcription factor GrlA is regulated by subcellular compartmentalization and activated in response to mechanical stimuli

2020 ◽  
Vol 117 (17) ◽  
pp. 9519-9528 ◽  
Author(s):  
Natalie Sirisaengtaksin ◽  
Max A. Odem ◽  
Rachel E. Bosserman ◽  
Erika M. Flores ◽  
Anne Marie Krachler
Keyword(s):  
Gastrointestinal Tract ◽  
Foodborne Pathogen ◽  
Virulence Gene ◽  
Adhesive Force ◽  
Mechanical Stimuli ◽  
Virulence Gene Expression ◽  
E Coli ◽  
Sense And Respond ◽  
Subcellular Compartmentalization ◽  
Enterocyte Effacement

Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen that colonizes the gastrointestinal tract and has evolved intricate mechanisms to sense and respond to the host environment. Upon the sensation of chemical and physical cues specific to the host’s intestinal environment, locus of enterocyte effacement (LEE)-encoded virulence genes are activated and promote intestinal colonization. The LEE transcriptional activator GrlA mediates EHEC’s response to mechanical cues characteristic of the intestinal niche, including adhesive force that results from bacterial adherence to epithelial cells and fluid shear that results from intestinal motility and transit. GrlA expression and release from its inhibitor GrlR was not sufficient to induce virulence gene transcription; mechanical stimuli were required for GrlA activation. The exact mechanism of GrlA activation, however, remained unknown. We isolated GrlA mutants that activate LEE transcription, independent of applied mechanical stimuli. In nonstimulated EHEC, wild-type GrlA associates with cardiolipin membrane domains via a patch of basic C-terminal residues, and this membrane sequestration is disrupted in EHEC that expresses constitutively active GrlA mutants. GrlA transitions from an inactive, membrane-associated state and relocalizes to the cytoplasm in response to mechanical stimuli, allowing GrlA to bind and activate the LEE1 promoter. GrlA expression and its relocalization in response to mechanical stimuli are required for optimal virulence regulation and colonization of the host intestinal tract during infection. These data suggest a posttranslational regulatory mechanism of the mechanosensor GrlA, whereby virulence gene expression can be rapidly fine-tuned in response to the highly dynamic spatiotemporal mechanical profile of the gastrointestinal tract.

scholarly journals Homeostatic Imbalance in Epithelial Ducts and Its Role in Carcinogenesis

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Katarzyna A. Rejniak
Keyword(s):  
Epithelial Cells ◽  
Biomechanical Model ◽  
Cell Polarization ◽  
Epithelial Tissue ◽  
Mechanical Stimuli ◽  
Relative Importance ◽  
Tissue Architecture ◽  
Multicellular Structure ◽  
Body Compartments

An epithelial duct is a well-defined multicellular structure composed of tightly packed cells separating and protecting body compartments that are used for enzyme secretion and its transport across the internal. The structural and functional integrity (homeostasis) of such ducts is vital in carrying many life functions (breathing, lactation, production of hormones). However, the processes involved in maintaining the homeostatic balance are not yet fully understood. On the other hand, the loss of epithelial tissue architecture, such as filled lumens or ductal disorganization, are among the first symptoms of the emerging epithelial tumors (carcinomas). Using the previously developed biomechanical model of epithelial ducts:IBCell, we investigated how different signals and mechanical stimuli imposed on individual epithelial cells can impact the homeostatic (im)balance and integrity of the whole epithelial tissue. We provide a link between erroneous responses of individual epithelial cells to specific signals and the emerging ductal morphologies characteristic for preinvasive cancers observed in pathology specimens, or characteristic for multicellular structures arising from mutated cells culturedin vitro. We summarize our finding in terms of altered properties of epithelial cell polarization, and discuss the relative importance of various polarization signals on the formation of tumor-like multicellular structures.

Parallel processing of tactile information in the cerebral cortex of the cat: effect of reversible inactivation of SI on responsiveness of SII neurons

1992 ◽  
Vol 67 (2) ◽  
pp. 411-429 ◽  
Author(s):  
A. B. Turman ◽  
D. G. Ferrington ◽  
S. Ghosh ◽  
J. W. Morley ◽  
M. J. Rowe
Keyword(s):  
Phase Locking ◽  
Receptive Fields ◽  
Mechanical Stimulus ◽  
Glabrous Skin ◽  
Mechanical Stimuli ◽  
Sinusoidal Vibration ◽  
Response Level ◽  
Reversible Inactivation ◽  
Stimulus Response ◽  
Cortical Cooling

1. Localized cortical cooling was employed in anesthetized cats for the rapid reversible inactivation of the distal forelimb region within the primary somatosensory cortex (SI). The aim was to examine the responsiveness of individual neurons in the second somatosensory area (SII) in association with SI inactivation to evaluate the relative importance for tactile processing of the direct thalamocortical projection to SII and the indirect projection from the thalamus to SII via an intracortical path through SI. 2. Response features were examined quantitatively before, during, and after SI inactivation for 29 SII neurons, the tactile receptive fields of which were on the glabrous or hairy skin of the distal forelimb. Controlled mechanical stimuli that consisted of l-s trains of either sinusoidal vibration or rectangular pulses were delivered to the skin by means of small circular probes (4- to 8-mm diam). 3. Twenty-three of the 29 SII neurons (80%) showed no change in response level (in impulses per second) as a result of SI inactivation. These included seven neurons activated exclusively or predominantly by Pacinian corpuscle (PC) receptors, six that received hair follicle input, four activated by convergent input from hairy and glabrous skin, and six driven by dynamically sensitive but non-PC inputs from the glabrous skin. 4. Six SII neurons (20%), also made up of different functional classes, displayed a reduction in response to cutaneous stimuli when SI was inactivated. 5. Stimulus-response relations, constructed by plotting response level in impulses per second against the amplitude of the mechanical stimulus, showed that the effect of SI inactivation on individual neurons was consistent over the whole response range. 6. The reduced response level seen in 20% of SII neurons in association with SI inactivation cannot be attributed to direct spread of cooling from SI to the forelimb area of SII, as there was no evidence for a cooling-induced prolongation in SII spike waveforms, an effect that is known to precede any cooling-induced reduction in responsiveness. 7. As SI inactivation produced a fall in spontaneous activity in the affected SII neurons, we suggest that the inactivation removes a source of background facilitatory influence that arises in SI and affects a small proportion of SII neurons. 8. Phase-locking and therefore the precision of impulse patterning were unchanged in the responses of SII neurons to vibration during SI inactivation. This was the case whether response levels of neurons were reduced or unchanged by SI inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)

A Study of Mechanosensing of an Osteoblast at Focal Adhesions Under Cyclic Strain Using Magnetic Micropillars

2019 ◽  
Author(s):  
Toshihiko Shiraishi ◽  
Kota Nagai
Keyword(s):  
Calcium Ion ◽  
Mechanical Vibration ◽  
Focal Adhesions ◽  
Cyclic Strain ◽  
Mechanical Stimuli ◽  
Osteoblast Cells ◽  
Intracellular Calcium Ion ◽  
A Cell ◽  
Sense And Respond ◽  
Biochemical Signals

Abstract It has been reported that cells sense and respond to mechanical stimuli. Mechanical vibration promotes the cell proliferation and the cell differentiation of osteoblast cells at 12.5 Hz and 50 Hz, respectively. It indicates that osteoblast cells have a mechansensing system for mechanical vibration. There may be some mechanosensors and we focus on cellular focal adhesions through which mechanical and biochemical signals may be transmitted from extracellular matrices into a cell. However, it is very difficult to directly apply mechanical stimuli to focal adhesions. We developed a magnetic micropillar substrate on which micron-sized pillars are deflected according to applied magnetic field strength and focal adhesions adhering to the top surface of the pillars are given mechanical stimuli. In this paper, we focus on intracellular calcium ion as a second messenger of cellular mechanosensing and investigate the mechanosensing mechanism of an osteoblast cell at focal adhesions under cyclic strain using a magnetic micropillar substrate. The experimental results indicate that the magnetic micropillars have enough performance to response to an electric current applied to a coil in an electromagnet and to apply the cyclic strain of less than 3% to a cell. In the cyclic strain of less than 3%, the calcium response of a cell was not observed.

Sign in / Sign up

Export Citation Format

Share Document