Search Results (14)

Caspases are known for their roles in cell death and inflammation. However, emerging evidence suggests they also mediate non-lethal processes, governed by a finely tuned balance of localization, activity, kinetics, and substrate availability. Given that many caspase substrates are implicated in mechanoadaptive processes, we investigated if caspases contribute to morphological adaptation of human pulmonary artery endothelial cells to fluid shear stress and other morphology-altering stimuli in vitro. Using selective inhibitors, we screened all major caspases for a role in endothelial cell adaptation to unidirectional laminar shear stress (15 dyn/cm², 72 h). Selective inhibition of caspase-6, but not other caspases, impaired morphological shear adaptation. Only 5.5% of caspase-6-inhibited cells shear-adapted vs. 75.2% of vector controls. Live-cell FRET imaging revealed progressive caspase-6 activation starting at 18 h of shear stress, coinciding with the onset of morphological remodeling. The active caspase-6 localized predominantly perinuclearly, while caspase-3 remained inactive throughout shear exposure. Caspase-6 inhibition did not affect elongation in response to alternative biomechanical or biochemical stimuli, including uniaxial cyclic stretch (5%, 1 Hz), spatial confinement on narrow micropatterned RGD-lines, or TNF-α stimulation, nor did it impair cell adhesion, directed migration, wound healing, or barrier recovery after wounding. Our study uncovers a previously unidentified role of caspase-6 as a non-apoptotic, mechanosensitive effector specifically required for shear-induced morphological adaptation of pulmonary artery endothelial cells, highlighting a novel regulatory axis in vascular mechanoadaptation. Full article

Orthodontic tooth movement (OTM) is a biologically orchestrated process involving the dynamic interplay of mechanical force, inflammatory signaling, and bone remodeling. Osteocytes, the most abundant cells within the bone matrix, serve as mechanosensitive regulators that transduce mechanical cues into biochemical signals in response to orthodontic force. This review delineates the multifaceted role of osteocytes in facilitating bone resorption required for OTM. The role of osteocytes is examined in inflammation, mechanical adaptation, and cell death. Additionally, we discuss the evidence on how aging alters osteocyte function, with senescence-associated changes disrupting mechanosensory networks and attenuating bone remodeling. Finally, the possibility that osteocytes themselves undergo morphological adaptation during force application is explored. This structural plasticity may impact individual variability in orthodontic outcomes. Advancing our understanding of osteocyte signaling in OTM holds significant promise for optimizing treatment outcomes across diverse patient populations. Full article

Advancements in load-bearing tissue repair increasingly demand biomaterials that not only support structural integrity but also interact dynamically with the physiological environment. This review examines the latest progress in smart biomaterials designed for skeletal reconstruction, with emphasis on mechanoresponsive scaffolds, bioactive composites, and integrated microsensors for real-time monitoring. We explore material formulations that enhance osseointegration, resist micromotion-induced loosening, and modulate inflammatory responses at the bone–implant interface. Additionally, we assess novel fabrication methods—such as additive manufacturing and gradient-based material deposition—for tailoring stiffness, porosity, and degradation profiles to match host biomechanics. Special attention is given to sensor-augmented platforms capable of detecting mechanical strain, biofilm formation, and early-stage implant failure. Together, these technologies promise a new class of bioresponsive, diagnostic-capable constructs that extend beyond static support to become active agents in regenerative healing and post-operative monitoring. This multidisciplinary review integrates insights from materials science, mechanobiology, and device engineering to inform the future of implantable systems in skeletal tissue repair. Full article

CAV1 is a protein-coding gene linked to several disorders, including cancer, lipodystrophy, and cardiovascular diseases. While its ability to respond to various mechanical and metabolic stimuli has been documented, a comprehensive understanding of its physiological regulation in humans is lacking. We leveraged the comprehensiveness of human post-mortem tissue data from the Genotype-Tissue Expression (GTEx) consortium, systematically exploring the sources of variability in CAV1 transcriptional levels using extensive bulk and single-nuclei RNA-seq datasets. This human-centric approach, avoiding inter-species comparisons, constitutes a unique resource to explore CAV1 regulation within the complexity of human tissues. Notably, cell type proportion was identified as a major determinant of CAV1 transcription levels across tissues. Donor physiological conditions, including disease states and end-of-life circumstances, also exhibited a tissue-specific influence. Among primary upstream regulators associated with CAV1, chromatin modifiers stood out, especially SMARCA2, which showed a positive correlation across tissues, and PRC2 complexes, which exhibited tissue-specific correlation. Upstream regulatory networks determining CAV1 levels are also enriched for annotations such as mechanobiology (e.g., TEAD4), immunity (e.g., RELA and STAT3), and metabolism (e.g., MYC and NRF1). A remarkable observation was a strong correlation between CAV1 and the relative infiltration of immune cells across tissues, supporting a potential role for CAV1 as a marker and driver of tissue immune infiltration. Full article

The plasma membrane (PM) is subjected to multiple mechanical forces, and it must adapt and respond to them. PM invaginations named caveolae, with a specific protein and lipid composition, play a crucial role in this mechanosensing and mechanotransduction process. They respond to PM tension changes by flattening, contributing to the buffering of high-range increases in mechanical tension, while novel structures termed dolines, sharing Caveolin1 as the main component, gradually respond to low and medium forces. Caveolae are associated with different types of cytoskeletal filaments, which regulate membrane tension and also initiate multiple mechanotransduction pathways. Caveolar components sense the mechanical properties of the substrate and orchestrate responses that modify the extracellular matrix (ECM) according to these stimuli. They perform this function through both physical remodeling of ECM, where the actin cytoskeleton is a central player, and via the chemical alteration of the ECM composition by exosome deposition. Here, we review mechanotransduction regulation mediated by caveolae and caveolar components, focusing on how mechanical cues are transmitted through the cellular cytoskeleton and how caveolae respond and remodel the ECM. Full article

High glucose (HG), a hallmark of the tumour microenvironment, is also a biomechanical stressor, as it exerts hyper-osmotic stress (HG-HO), but not much is known regarding how tumour cells mechanoadapt to HG-HO. Therefore, this study aimed to delineate the novel molecular mechanisms by which tumour cells mechanoadapt to HG/HG-HO and whether phytochemical-based interference in these mechanisms can generate tumour-cell-selective vulnerability to cell death. Mannitol and L-glucose were used as hyper-osmotic equivalents of high glucose. The results revealed that the tumour cells can efficiently mechanoadapt to HG-HO only in the normoxic microenvironment. Under normoxic HG/HG-HO stress, tumour cells polySUMOylate a higher pool of mitotic driver pH3(Ser10), which translocates to the nucleus and promotes faster cell divisions. On the contrary, acute hypoxia dampens HG/HG-HO-associated excessive proliferation by upregulating sentrin protease SENP7. SENP7 promotes abnormal SUMOylation of pH3(Ser10), thereby restricting its nuclear entry and promoting the M-phase arrest and cell loss. However, the hypoxia-arrested cells that managed to survive showed relapse upon reversal to normoxia as well as upregulation of pro-survival-associated SENP1, and players in tumour growth signalling, autophagy, glycolytic pathways etc. Depletion of SENP1 in both normoxia and hypoxia caused significant loss of tumour cells vs undepleted controls. SENP1 was ascertained to restrict the abnormal SUMOylation of pH3(Ser10) in both normoxia and hypoxia, although not so efficiently in hypoxia, due to the opposing activity of SENP7. Co-treatment with Momordin Ic (MC), a natural SENP1 inhibitor, and Gallic Acid (GA), an inhibitor of identified major pro-tumourigenic signalling (both enriched in Momordica charantia), eliminated surviving tumour cells in normal glucose, HG and HG-HO normoxic and hypoxic microenvironments, suggesting that appropriate and enhanced polySUMOylation of pH3(Ser10) in response to HG/HG-HO stress was attenuated by this treatment along with further dampening of other key tumourigenic signalling, due to which tumour cells could no longer proliferate and grow. Full article

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. In addition to genetic causes, the tumor microenvironment (TME), including stiffening of the extracellular matrix (ECM), is a main driver of GBM progression. Mechano-transduction and the unfolded protein response (UPR) are essential for tumor-cell adaptation to harsh TME conditions. Here, we studied the effect of a variable stiff ECM on the morphology and malignant properties of GBM stem cells (GSCs) and, moreover, examined the possible involvement of the UPR sensor PERK herein. For this, stiffness-tunable human blood plasma (HBP)/alginate hydrogels were generated to mimic ECM stiffening. GSCs showed stiffness-dependent adaptation characterized by elongated morphology, increased proliferation, and motility which was accompanied by F-Actin cytoskeletal remodeling. Interestingly, in PERK-deficient GSCs, stiffness adaptation was severely impaired, which was evidenced by low F-Actin levels, the absence of F-Actin remodeling, and decreased cell proliferation and migration. This impairment could be linked with Filamin-A (FLN-A) expression, a known interactor of PERK, which was strongly reduced in PERK-deficient GSCs. In conclusion, we identified a novel PERK/FLNA/F-Actin mechano-adaptive mechanism and found a new function for PERK in the cellular adaptation to ECM stiffening. Full article

Cells have adapted to mechanical forces early in evolution and have developed multiple mechanisms ensuring sensing of, and adaptation to, the diversity of forces operating outside and within organisms. The nucleus must necessarily adapt to all types of mechanical signals, as its functions are essential for virtually all cell processes, many of which are tuned by mechanical cues. To sense forces, the nucleus is physically connected with the cytoskeleton, which senses and transmits forces generated outside and inside the cell. The nuclear LINC complex bridges the cytoskeleton and the nuclear lamina to transmit mechanical information up to the chromatin. This system creates a force-sensing macromolecular complex that, however, is not sufficient to regulate all nuclear mechanoadaptation processes. Within the nucleus, additional mechanosensitive structures, including the nuclear envelope and the nuclear pore complex, function to regulate nuclear mechanoadaptation. Similarly, extra nuclear mechanosensitive systems based on plasma membrane dynamics, mechanotransduce information to the nucleus. Thus, the nucleus has the intrinsic structural components needed to receive and interpret mechanical inputs, but also rely on extra nuclear mechano-sensors that activate nuclear regulators in response to force. Thus, a network of mechanosensitive cell structures ensures that the nucleus has a tunable response to mechanical cues. Full article

Directional root growth control is crucial for plant fitness. The degree of root growth deviation depends on several factors, whereby exogenous growth conditions have a profound impact. The perception of mechanical impedance by wild-type roots results in the modulation of root growth traits, and it is known that gravitropic stimulus influences distinct root movement patterns in concert with mechanoadaptation. Mutants with reduced shootward auxin transport are described as being numb towards mechanostimulus and gravistimulus, whereby different growth conditions on agar-supplemented medium have a profound effect on how much directional root growth and root movement patterns differ between wild types and mutants. To reduce the impact of unilateral mechanostimulus on roots grown along agar-supplemented medium, we compared the root movement of Col-0 and auxin resistant 1-7 in a root penetration assay to test how both lines adjust the growth patterns of evenly mechanostimulated roots. We combined the assay with the D-root system to reduce light-induced growth deviation. Moreover, the impact of sucrose supplementation in the growth medium was investigated because exogenous sugar enhances root growth deviation in the vertical direction. Overall, we observed a more regular growth pattern for Col-0 but evaluated a higher level of skewing of aux1-7 compared to the wild type than known from published data. Finally, the tracking of the growth rate of the gravistimulated roots revealed that Col-0 has a throttling elongation rate during the bending process, but aux1-7 does not. Full article

Autophagy and the lysosomal system, together referred to as the autophagolysosomal system, is a cellular quality control network which maintains cellular health and homeostasis by removing cellular waste including protein aggregates, damaged organelles, and invading pathogens. As such, the autophagolysosomal system has roles in a variety of pathophysiological disorders, including cancer, neurological disorders, immune- and inflammation-related diseases, and metabolic alterations, among others. The autophagolysosomal system is controlled by TFEB, a master transcriptional regulator driving the expression of multiple genes, including autophagoly sosomal components. Importantly, Reactive Oxygen Species (ROS) production and control are key aspects of the physiopathological roles of the autophagolysosomal system, and may hold a key for synergistic therapeutic interventions. In this study, we reviewed our current knowledge on the biology and physiopathology of the autophagolysosomal system, and its potential for therapeutic intervention in cancer. Full article

Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities. Full article

Formation of a barrier capable of protecting tissue from external damage, chemical factors, and pathogens is one of the main functions of the epidermis. Furthermore, upon development and during aging, mechanoprotective epidermal functions change dramatically. However, comparative studies between embryonic and adult skin in comparison to skin equivalents are still scarce which is especially due to the lack of appropriate measurement systems with sufficient accuracy and long-term tissue compatibility. Our studies fill this gap by developing a combined bioreactor and tensile testing machine for biomechanical analysis of living epithelia. Based on this tissue stretcher, our data clearly show that viscoelastic and plastic deformation behavior of embryonic and adult skin differ significantly. Tissue responses to static strain compared to cyclic strain also show a clear dependence on differentiation stage. Multilayered unkeratinized epidermis equivalents, on the other hand, respond very similar to mechanical stretch as adult tissue. This mechanical similarity is even more evident after a single cycle of mechanical preconditioning. Our studies therefore suggest that skin equivalents are well suited model systems to analyze cellular interactions of epidermal cells in natural tissues. Full article

Tumor metastasis involves the dissemination of tumor cells from the primary lesion to other organs and the subsequent formation of secondary tumors, which leads to the majority of cancer-related deaths. Clinical findings show that cancer cell dissemination is not random but exhibits organ preference or organotropism. While intrinsic biochemical factors of cancer cells have been extensively studied in organotropism, much less is known about the role of cell cytoskeleton and mechanics. Herein, we demonstrate that cell cytoskeleton and mechanics are correlated with organotropism. The result of cell stiffness measurements shows that breast cancer cells with bone tropism are much stiffer with enhanced F-actin, while tumor cells with brain tropism are softer with lower F-actin than their parental cells. The difference in cellular stiffness matches the difference in the rigidity of their metastasized organs. Further, disrupting the cytoskeleton of breast cancer cells with bone tropism not only elevates the expressions of brain metastasis-related genes but also increases cell spreading and proliferation on soft substrates mimicking the stiffness of brain tissue. Stabilizing the cytoskeleton of cancer cells with brain tropism upregulates bone metastasis-related genes while reduces the mechanoadaptation ability on soft substrates. Taken together, these findings demonstrate that cell cytoskeleton and biophysical properties of breast cancer subpopulations correlate with their metastatic preference in terms of gene expression pattern and mechanoadaptation ability, implying the potential role of cell cytoskeleton in organotropism. Full article

The regulation of Reactive Oxygen Species (ROS) levels and the contribution therein from networks regulating cell metabolism, such as autophagy and the mTOR-dependent nutrient-sensing pathway, constitute major targets for selective therapeutic intervention against several types of tumors, due to their extensive rewiring in cancer cells as compared to healthy cells. Here, we discuss the sestrin family of proteins—homeostatic transducers of oxidative stress, and drivers of antioxidant and metabolic adaptation—as emerging targets for pharmacological intervention. These adaptive regulators lie at the intersection of those two priority nodes of interest in antitumor intervention—ROS control and the regulation of cell metabolism and autophagy—therefore, they hold the potential not only for the development of completely novel compounds, but also for leveraging on synergistic strategies with current options for tumor therapy and classification/stadiation to achieve personalized medicine. Full article