Search Results (469)

The Hippo pathway is highly evolved to maintain tissue homeostasis in diverse species by regulating cell proliferation, differentiation, and apoptosis. In tumor biology, the Hippo pathway is a prime example of signaling molecules involved in cancer progression and metastasis. Hippo core elements LATS1, LATS2, MST1, YAP, and TAZ have critical roles in the maintenance of traditional tissue architecture and cell homeostasis. However, in cancer development, dysregulation of Hippo signaling results in tumor progression and the formation secondary cancers. Hippo components not only transmit biochemical signals but also act as mediators of mechanotransduction pathways during malignant neoplasm development and metastatic disease. This review confers knowledge of Hippo pathway core components and their role in cancer progression and metastasis and highlights the clinical role of Hippo pathway in cancer treatment. The Hippo signaling pathway and its unresolved mechanisms hold great promise as potential therapeutic targets in the emerging field of metastatic cancer research. Full article

Competitive athletes are often exposed to extreme physiological loading, resulting in over excessive mechanotransduction during their acute intensive training sessions and competitions. Individual differences in their genetics often affect how they cope with these challenges, as reflected in their high performances. Olympic Medalists are prohibited from providing atypical values in the Hematological Module of the Athlete Biological Passport. Since there was no aphysiological result and the Athlete maintained his innocence, a whole genome sequence analysis was carried out on him and his parents, with the primary focus on the PIEZO ion channels encoding gene. PIEZO1 is known to participate in homeostatic regulation even on a whole-body level, including the regulation of physical performance, circulatory longevity of red blood cells and cell fate determination of mesenchymal stem cells in relation to hydrostatic pressure. However, PIEZO2 was found to be the principal mechanosensory ion channel for proprioception. These regulatory mechanisms play a pivotal role in mechanotransduction and intensive exercise moments. Interestingly, two variances of uncertain significance of PIEZO1 were found that may explain the atypical values of the Athlete. Furthermore, two additional variances in SDC2, the syndcan-2 encoding gene, were identified in trans position that may influence the crosstalk between PIEZO2 and PIEZO1, with more likely relevance to the detected atypical values. After all, based on the found variances of PIEZO1 and syndecan-2, it cannot be ruled out that these VUS variants may have caused or impacted the exhibited outlier findings of the ABP Hematological Module of the Athlete. Full article

Fibrosis is characterized by scarring and hardening of tissues and organs. It can affect every organ system, and so could result in organ failure due to the accumulation of extracellular matrix proteins. Previous studies suggest that mechanical forces (such as shockwave therapy, SWT) initiate a process of mechanotransduction and thus could regulate fibrosis. Nevertheless, it is largely unexamined which pathways are exactly involved in the application of SWT and can regulate fibrosis. The present article seeks to elucidate the underlying effect of SWT on fibrosis. Evidence shows that SWT activates macrophage activity, fibroblast activity, collagen amount and orientation and apoptosis, which ultimately lead to an adaptation of inflammation, proliferation, angiogenesis and apoptosis. The included articles reveal that other proteins and pathways can be activated depending on the energy levels and frequency of SWT. These findings demonstrate that SWT has beneficial effects on fibrosis by influencing the proteins and pathways. Based on these data, which highlights the underlying mechanisms, we can make preliminary conclusions about the treatment modalities of SWT in scar formation, such as the energy levels and frequencies that are necessary to prevent or treat fibrotic tissue. Full article

This review explores the regenerative capacity of Xenopus laevis, focusing on tail regeneration, as a model to uncover cellular, molecular, and developmental mechanisms underlying tissue repair. X. laevis tadpoles provide unique insights into regenerative biology due to their regeneration-competent and -incompetent stages and ability to regrow complex structures in the tail, including the spinal cord, muscle, and skin, after amputation. The review delves into the roles of key signaling pathways, such as those involving reactive oxygen species (ROS) and signaling molecules like BMPs and FGFs, in orchestrating cellular responses during regeneration. It also examines how mechanotransduction, epigenetic regulation, and metabolic shifts influence tissue restoration. Comparisons of regenerative capacity with other species shed light on the evolutionary loss of regenerative abilities and underscore X. laevis as an invaluable model for understanding the constraints of tissue repair in higher organisms. This comprehensive review synthesizes recent findings, suggesting future directions for exploring regeneration mechanisms, with potential implications for advancing regenerative medicine. Full article

Transient receptor potential vanilloid (TRPV) channel proteins belong to the superfamily of TRP proteins that form cationic channels in the animal cell membranes. These proteins have various subtype-specific functions, serving, for example, as sensors for pain, pressure, pH, and mechanical extracellular stimuli. The sensing of extracellular cues by TRPV4 triggers Ca²⁺-influx through the channel, subsequently coordinating numerous intracellular signaling cascades in a spatio-temporal manner. As TRPV channels play such a wide role in various cellular and physiological functions, loss or impaired TRPV protein activity naturally contributes to many pathophysiological processes. This review concentrates on the known functions of TRPV4 sensor proteins and their potential as a therapeutic target. Full article

Mechanotransduction, the process of how cells sense and convert mechanical stimuli into biochemical response, is crucial in the migration of leukocytes or cancer cells through the endothelium during inflammation or metastasis. Migrating cells exert forces on the endothelium through cell surface adhesion molecules, such as platelet endothelial adhesion molecule PECAM-1, and this is essential for a successful transmigration. To study PECAM-1-mediated mechanotransduction, we applied PECAM-1-antibody-coated magnetic beads and exerted about 40 pN force on the endothelial monolayer. We show that force increases cell–ECM adhesion in the cell center and is accompanied by the opening of cell–cell junctions. Upon depletion of the MEK/ERK kinase, BRAF force increases cell–ECM adhesion both at the cell periphery and in the cell center, but this does not result in the opening of cell–cell junctions. Decreasing cell–ECM adhesion in BRAF-depleted cells through FAK inhibition results in the remodeling of cell–cell junctions. Force-induced increase in cell–ECM adhesion in the cell center correlates with the activation of the transcriptional cofactor Yes-associated protein (YAP). Furthermore, the induced activation of YAP through LATS inhibition prevents junctional remodeling in control cells. Thus, the activation of YAP might determine the strength of cell–cell junctions during PECAM-1-mediated mechanotransduction. Full article

Emotional communication is a multi-modal phenomenon involving posture, gestures, facial expressions, and the human voice. Affective states systematically modulate the acoustic signals produced during speech production through the laryngeal muscles via the central nervous system, transforming the acoustic signal into a means of affective transmission. Additionally, a substantial body of research in sonobiology has shown that audible acoustic waves (AAW) can affect cellular dynamics. This pilot study explores whether the physical–acoustic changes induced by gratitude states in human speech could influence cell proliferation and Ki67 expression in non-auditory cells (661W cell line). We conduct a series of assays, including affective electroencephalogram (EEG) measurements, an affective text quantification algorithm, and a passive vibro-acoustic treatment (PVT), to control the CO₂ incubator environment acoustically, and a proliferation assay with immunolabeling to quantify cell dynamics. Although a larger sample size is needed, the hypothesis that emotions can act as biophysical agents remains a plausible possibility, and feasible physical and biological pathways are discussed. In summary, studying the impact of gratitude AAW on cell biology represents an unexplored research area with the potential to enhance our understanding of the interaction between human cognition and biology through physics principles. Full article

Myocardial infarction and reperfusion constitute a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling, which is essential to cardiac development, also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here, we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. We found that Yap, and not Taz, expression patterns differed in a post-myocardial infarct compared to a peri-infarct region of rat hearts post-myocardial infarction, suggesting cell specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were determined to be more sensitive to nutrient deprivation than other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, predominantly L-isoleucine, and influences the expression of connective tissue growth factor (Ctgf)—a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation. Full article

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA. Full article

Mechanosensing and mechanotransduction pathways between the Extracellular Matrix (ECM) and cells form the essential crosstalk that regulates cell homeostasis, tissue development, morphology, maintenance, and function. Understanding these mechanisms involves creating an appropriate cell support that elicits signals to guide cellular functions. In this context, polymers can serve as ideal molecules for producing biomaterials designed to mimic the characteristics of the ECM, thereby triggering responsive mechanisms that closely resemble those induced by a natural physiological system. The generated specific stimuli depend on the different natural or synthetic origins of the polymers, the chemical composition, the assembly structure, and the physical and surface properties of biomaterials. This review discusses the most widely used polymers and their customization to develop biomaterials with tailored properties. It examines how the characteristics of biomaterials-based polymers can be harnessed to replicate the functions of biological cells, making them suitable for biomedical and biotechnological applications. Full article

Background: Keloids are a common fibrotic disease of the skin, with the pathological hallmark of excessive extracellular matrix synthesis due to abnormal fibroblast activity. Since keloids clinically arise in areas of high mechanical tension, the mechanotransductory pathway may be attributed to its pathogenesis. We aimed to establish a preclinical platform to elucidate the underlying mechanism of keloid development and its clinical persistence. Methods: We fabricated a mechanically stretchable polydimethylsiloxane cell culture platform; with its mimicry of the in vivo cyclic stretch of skeletal muscles, cells showed higher proliferation compared with conventional modalities. Results: In response to mechanical strain, TGF-β and type 1 collagen showed significant increases, suggesting possible TGF-β/Smad pathway activation via mechanical stimulation. Protein candidates selected by proteomic analysis were evaluated, indicating that key molecules involved in cell signaling and oxidative stress were significantly altered. Additionally, the cytoskeletal network of keloid fibroblasts showed increased expression of its components after periodic mechanical stimulation. Conclusions: Herein, we demonstrated and validated the existing body of knowledge regarding profibrotic mechanotransduction signaling pathways in keloid fibroblasts. Cyclic stretch, as a driving force, could help to decipher the tension-mediated biomechanical processes, leading to the development of optimized therapeutic targets. Full article

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation. Full article

Purpose: Glaucoma, one of the leading causes of irreversible blindness, is a common progressive optic neuropathy characterised by visual field defects and structural changes to the optic nerve head (ONH). There is extracellular matrix (ECM) accumulation and fibrosis of the lamina cribrosa (LC) in the ONH, and consequently increased tissue stiffness of the LC connective tissue. Integrins are cell surface proteins that provide the key molecular link connecting cells to the ECM and serve as bidirectional sensors transmitting signals between cells and their environment to promote cell adhesion, proliferation, and remodelling of the ECM. Here, we investigated the expression of αVβ3 integrin in glaucoma LC cell, and its effect on stiffness-induced ECM gene transcription and cellular proliferation rate in normal (NLC) and glaucoma (GLC) LC cells, by down-regulating αVβ3 integrin expression using cilengitide (a known potent αVβ3 and αVβ5 inhibitor) and β3 integrin siRNA knockdown. Methods: GLC cells were compared to age-matched controls NLC to determine differential expression levels of αVβ3 integrin, ECM genes (Col1A1, α-SMA, fibronectin, vitronectin), and proliferation rates. The effects of αVβ3 integrin blockade (with cilengitide) and silencing (with a pool of four predesigned αVβ3 integrin siRNAs) on ECM gene expression and proliferation rates were evaluated using both reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting in the human NLC cells cultured on soft (4 kPa) and stiff (100 kPa) substrate and in GLC cells grown on standard plastic plates. Results: αVβ3 integrin gene and protein expression were enhanced (p < 0.05) in GLC cells as compared to NLC. Both cilengitide and siRNA significantly reduced αVβ3 expression in GLC. When NLC were grown in the stiff substrate, cilengitide and siRNA also significantly reduced the increased expression in αVβ3, ECM components, and proliferation rate. Conclusions: Here, we provide evidence of cilengitide- and siRNA-mediated silencing of αVβ3 integrin expression, and inhibition of ECM synthesis in LC cells. Therefore, αVβ3 integrin may be a promising target for the development of novel anti-fibrotic therapies for treating the LC cupping of the ONH in glaucoma. Full article

Mechanical force is the basis of cardiovascular development, homeostasis, and diseases. The perception and response of mechanical force by the cardiovascular system are crucial. However, the molecular mechanisms mediating mechanotransduction in the cardiovascular system are not yet understood. PIEZO1, a novel transmembrane mechanosensitive cation channel known for its regulation of touch sensation, has been found to be widely expressed in the mammalian cardiovascular system. In this review, we elucidate the role and mechanism of PIEZO1 as a mechanical sensor in cardiovascular development, homeostasis, and disease processes, including embryo survival, angiogenesis, cardiac development repair, vascular inflammation, lymphangiogenesis, blood pressure regulation, cardiac hypertrophy, cardiac fibrosis, ventricular remodeling, and heart failure. We further summarize chemical molecules targeting PIEZO1 for potential translational applications. Finally, we address the controversies surrounding emergent concepts and challenges in future applications. Full article

Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins’ potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins’ colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems. Full article