Shuffling the cards in signal transduction: Calcium, arachidonic acid and mechanosensitivity

Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own structure but also on its connections with other biomolecules. During prokaryotic-eukaryotic transition, the rearrangement of cell organization in terms of diffusional compartmentalization exerts a deep change in cell signaling functional potentiality. In this review I briefly introduce an intriguing ancient relationship between pathways involved in cell responses to chemical agonists (growth factors, nutrients, hormones) as well as to mechanical forces (stretch, osmotic changes). Some biomolecules (ion channels and enzymes) act as "hubs", thanks to their ability to be directly or indirectly chemically/mechanically co-regulated. In particular calcium signaling machinery and arachidonic acid metabolism are very ancient networks, already present before eukaryotic appearance. A number of molecular "hubs", including phospholipase A2 and some calcium channels, appear tightly interconnected in a cross regulation leading to the cellular response to chemical and mechanical stimulations.

Mechanics of mechanosensitivity of cell

Focal adhesions(FAs) are large,multiprotein complexs that provides linkers between cytoskeleton to the extracellular matrix(ECM).Cells sense and respond to forces through FAs to regulate a broad range of processes,such as cell growth,migration,differentiation

Mechanics of mechanosensitivity of cell

Cells sense and respond to forces and extracellular environment through FAs to regulate a broad range of processes, such as cell growth,migration,differentiation and apoptosis. Currently,the underlying mechanisms of the force

Mathematical Modeling of Cardiomyocytes’ and Skeletal Muscle Fibers’ Membrane: Interaction with External Mechanical Field

We propose a mathematic model of muscle cell membrane based on thin-walled elastic rod theory. A deformation occurs in rodents’ skeletal and cardiac cells during a period of antiorthostatic suspension. We carried out a quantitative evaluation of the deformation using this model. The calculations showed the deformation in cardiac cells to be greater than in skeletal ones. This data corresponds to experimental results of cell response that appears intense in cardiomyocytes than in skeletal muscle cells. Moreover, the deformation in skeletal and heart muscle cells has a different direction (stretching vs. compression), corresponding to experimental data of different adaptive response generation pathways in cells because of external mechanical condition changes.

Osteocyte pericellular and perilacunar matrices as markers of bone-implant mechanical integrity

To develop durable bone healing strategies through improved control of bone repair,it is of critical importance to understand the mechanisms of bone mechanical integrity when in contact with biomaterials and implants.Bone mechanical integrity is defined here as the adaptation of structural properties of remodeled bone in regard to an applied mechanical loading.Accordingly,the authors present why future investigations in bone repair and regeneration should emphasize on the matrix surrounding the osteocytes.Osteocytes are mechanosensitive cells considered as the orchestrators of bone remodeling,which is the biological process involved in bone homeostasis.These bone cells are trapped in an interconnected porous network,the lacunocanalicular network,which is embedded in a bone mineralized extracellular matrix.As a consequence of an applied mechanical loading,the bone deformation results in the deformation of this lacunocanalicular network inducing a shift in interstitial fluid pressure and velocity,thus resulting in osteocyte stimulation.The material environment surrounding each osteocyte,the so called perilacunar and pericellular matrices properties,define its mechanosensitivity.While this mechanical stimulation pathway is well known,the laws used to predict bone remodeling are based on strains developing at a tissue scale,suggesting that these strains are related to the shift in fluid pressure and velocity at the lacunocanalicular scale.While this relationship has been validated through observation in healthy bone,the fluid behavior at the bone-implant interface is more complex.The presence of the implant modifies fluid behavior,so that for the same strain at a tissue scale,the shift in fluid pressure and velocity will be different than in a healthy bone tissue.In that context,new markers for bone mechanical integrity,considering fluid behavior,have to be defined.The viewpoint exposed by the authors indicates that the properties of the pericellular and the perilacunar matrices have to be systematically investigated and used as structural markers of fluid behavior in the course of bone biomaterial development.

Mathematical Modeling in Cell Biomechanics: Myofibrils Contractile Activity

Cell as elastic rod behavior model is proposed to describe its contractile activity. The model takes into account the result of the transduction of external influences, which is resulting in the formation of internal deformation, and evaluates the mobility and/or the tension in the muscle cells under the external influence.

On the gating of mechanosensitive channels by fluid shear stress

Mechanosensation is an important process in biological fluid–structure interaction. To understand the biophysics underlying mechanosensation, it is essential to quantify the correlation between membrane deformation,membrane tension, external fluid shear stress, and conformation of mechanosensitive(MS) channels. Smoothed dissipative particle dynamics(SDPD) simulations of vesicle/cell in three types of flow configurations are conducted to calculate the tension in lipid membrane due to fluid shear stress from the surrounding viscous flow. In combination with a simple continuum model for an MS channel, SDPD simulation results suggest that shearing adhered vesicles/cells is more effective to induce membrane tension sufficient to stretch MS channels open than a free shear flow or a constrictive channel flow. In addition, we incorporate the bilayer–cytoskeletal interaction in a two-component model to probe the effects of a cytoskeletal network on the gating of MS channels.

Multi-scale molecular dynamics simulations and applications on mechanosensitive proteins of integrins

Molecular dynamics simulation(MDS)is a powerful technology for investigating evolution dynamics of target proteins,and it is used widely in various fields from materials to biology.This mini-review introduced the principles,main preforming procedures,and advances of MDS,as well as its applications on the studies of conformational and allosteric dynamics of proteins especially on that of the mechanosensitive integrins.Future perspectives were also proposed.This review could provide clues in understanding the potentiality of MD simulations in structure–function relationship investigation of biological proteins.

Mechanical force and cytoplasmic Ca^(2+) activate mechanosensitive BK channel in parallel

BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[1].Recently, the BK channels have

Recent advances of mechanosensitive genes in vascular endothelial cells for the formation and treatment of atherosclerosis

Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide.Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells,and it plays an important role in gene regulation of pro-inflammatory,pro-thrombotic,pro-oxidative stress,and cell permeability.Many impor-tant endothelial cell mechanosensitive genes have been discovered,including KLK10,CCN gene family,NRP2,YAP,TAZ,HIF-1α,NF-kB,FOS,JUN,TFEB,KLF2/KLF4,NRF2,and ID1.Some of them have been intensively studied,whereas the relevant regulatory mechanism of other genes remains unclear.Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease.Thus,this article reviews the mechanosensitive genes affecting vascular endothelial cells,including classical pathways and some newly screened genes,and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights foranti-atherosclerosis.

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain

Post-amputation pain causes great sufering to amputees,but still no efective drugs are available due to its elusive mechanisms.Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump efectively relieves the phantom pain aficting patients after amputation.This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain(CPAP).However,the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery.In this study,we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infltrated into the dorsal root ganglion(DRG)neurons worked synergistically to promote CPAP.Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG,and the expression of TMEM63A increased signifcantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer(TNT).Behavioral tests showed that the mechanical,heat,and cold sensitivity were not afected in the Tmem63a-/-mice in the naïve state,suggesting the basal pain was not afected.In the infammatory and post-amputation state,the mechanical allodynia but not the heat hyperalgesia or cold allodynia was signifcantly decreased in Tmem63a-/-mice.Further study showed that there was severe neuronal injury and macrophage infltration in the DRG,tibial nerve,residual stump,and the neuromalike structure of the TNT mouse model,Consistent with this,expression of the pro-infammatory cytokines TNFα,IL-6,and IL-1βall increased dramatically in the DRG.Interestingly,the deletion of Tmem63a signifcantly reduced the macrophage infltration in the DRG but not in the tibial nerve stump.Furthermore,the ablation of macrophages signifcantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model,indicating an interaction between nociceptors and macrophages,and that these two factors gang up together to regulate the formation of CPAP.This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Nanotopographic micro-nano forces finely tune the conformation of macrophage mechanosensitive membrane protein integrinβ_(2)to manipulate inflammatory responses

Finely tuning mechanosensitive membrane proteins holds great potential in precisely controlling inflammatory responses.In addition to macroscopic force,mechanosensitive membrane proteins are reported to be sensitive to micro-nano forces.Integrinβ_(2),for example,might undergo a piconewton scale stretching force in the activation state.High-aspect-ratio nanotopographic structures were found to generate nN-scale biomechanical force.Together with the advantages of uniform and precisely tunable structural parameters,it is fascinating to develop low-aspect-ratio nanotopographic structures to generate micro-nano forces for finely modulating their conformations and the subsequent mechanoimmiune responses.In this study,low-aspect-ratio nanotopographic structures were developed to finely manipulate the conformation of integrinβ_(2).The direct interaction of forces and the model molecule integrinαXβ_(2)was first performed.It was demonstrated that pressing force could successfully induce conformational compression and deactivation of integrinαXβ_(2),and approximately 270 to 720 pN may be required to inhibit its conformational extension and activation.Three low-aspect-ratio nanotopographic surfaces(nanohemispheres,nanorods,and nanoholes)with various structural parameters were specially designed to generate the micro-nano forces.It was found that the nanorods and nanohemispheres surfaces induce greater contact pressure at the contact interface between macrophages and nanotopographic structures,particularly after cell adhesion.These higher contact pressures successfully inhibited the conformational extension and activation of integrinβ_(2),suppressing focal adhesion activity and the downstream PI3K-Akt signaling pathway,reducing NF-κB signaling and macrophage inflammatory responses.Our findings suggest that nanotopographic structures can be used to finely tune mechanosensitive membrane protein conformation changes,providing an effective strategy for precisely modulating inflammatory responses.

Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes

Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes.Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.

Overexpression of mechanical sensitive miR-337-3p alleviates ectopic ossification in rat tendinopathy model via targeting IRS1 and Nox4 of tendon-derived stem cells

Tendinopathy,which is characterized by the ectopic ossification of tendon,is a common disease occurring in certain population,such as athletes that suffer from repetitive tendon strains.However,the molecular mechanism underlying the pathogenesis of tendinopathy caused by the overuse of tendon is still lacking.Here,we found that the mechanosensitive miRNA,miR-337-3p,had lower expression under uniaxial cyclical mechanical loading in tendon-derived stem cells(TDSCs)and negatively controlled chondro-osteogenic differentiation of TDSCs.Importantly,downregulation of miR-337-3p expression was also observed in both rat and human calcified tendons,and overexpressing miR-337-3p in patellar tendons of rat tendinopathy model displayed a robust therapeutic efficiency.Mechanistically,we found that the proinflammatory cytokine interleukin-1^was the upstream factor of miR-337-3p that bridges the mechanical loading with its downregulation.Furthermore,the target genes of miR-337-3p,NADPH oxidase 4,and insulin receptor substrate 1,activated chondro-osteogenic differentiation of TDSCs through JNK and ERK signaling,respectively.Thus,these findings not only provide novel insight into the molecular mechanisms underlying ectopic ossification in tendinopathy but also highlight the significance of miR-337-3p as a putative therapeutic target for clinic treatment of tendinopathy.