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At least 19 recordsLinked to original sources
PubMed2025

CAFs activated by YAP1 upregulate cancer matrix stiffness to mediate hepatocellular carcinoma progression.

BACKGROUND: The stiffness of the matrix is closely related to the progression of hepatocellular carcinoma (HCC). Although direct targeting of stromal rigidity in HCC remains a clinical challenge, cancer-associated fibroblasts (CAFs) are considered key contributors to this process. Given the heterogeneity of CAFs, this study explored the relationship between specific CAF subsets and liver cancer matrix stiffness, aiming to identify novel therapeutic targets for HCC patients. METHODS: Single-cell sequencing datasets were leveraged to identify cell types within liver cancer and characterize the transcriptomic profiles of CAFs. Prognostic analysis, utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) liver cancer datasets, assessed the correlation between matrix stiffness-related genes and HCC patient outcomes. Pseudo-time analysis was applied to trace the developmental trajectories of CAFs. By calculating intercellular communication probabilities and analyzing transcription factor activity, the functions and interactions of different CAF subsets were elucidated. Gene Ontology (GO) analysis was used to explore the functional roles of CAFs in distinct Yes-associated protein 1 (YAP1) groups. Finally, cellular experiments and animal experiments were further conducted to validate the hypotheses of this study. RESULTS: This study identified CAF subpopulations based on single-cell sequencing data and analyzed transcriptional changes within these subpopulations. Key findings include the identification of collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and lysyloxidase (LOX) as pivotal node genes during CAF development. Moreover, the expression of matrix stiffness-related genes was inversely correlated with the prognosis of HCC patients. Notably, the YAP1-positive CAF subpopulation emerged as the primary contributor to matrix stiffness in liver cancer. This subpopulation upregulates the expression of matrix stiffness-related genes and promotes tumor progression by activating signaling pathways such as autophagy and GTPase activity regulation. Cellular experiments and animal studies further validated this conclusion. CONCLUSION: This single-cell analysis uncovered the functional roles of CAFs in liver cancer. The YAP1-positive CAF subpopulation, in particular, was shown to contribute to matrix stiffness by upregulating the expression of relevant genes and promoting tumor progression through the activation of specific signaling pathways.

Carcinoma, Hepatocellular↗
PubMed2016

Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression.

The mechanical environment is crucial for intervertebral disc degeneration (IDD). However, the mechanisms underlying the regulation of cartilage endplate (CEP) calcification by altered matrix stiffness remain unclear. In this study, we found that matrix stiffness of CEP was positively correlated with the degree of IDD, and stiff matrix, which mimicked the severe degeneration of CEP, promoted inorganic phosphate-induced calcification in CEP chondrocytes. Co-expression analysis of the miRNA and mRNA profiles showed that increasing stiffness resulted in up-regulation of miR-20a and down-regulation of decreased ankylosis protein homolog (ANKH) during inorganic phosphate-induced calcification in CEP chondrocytes. Through a dual luciferase reporter assay, we confirmed that miR-20a directly targets 3'-untranslated regions of ANKH. The inhibition of miR-20a attenuated the calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhanced calcification in CEP chondrocytes on stiff matrix. The rescue of ANKH expression restored the decreased pyrophosphate efflux and inhibited calcification. In clinical samples, the levels of ANKH expression were inversely associated with the degeneration degree of CEP. Thus, our findings demonstrate that the miR-20a/ANKH axis mediates the stiff matrix- promoted CEP calcification, suggesting that miR-20a and ANKH are potential targets in restraining the progression of IDD.

3' Untranslated Regions↗
PubMed2025

Interrogating functional connectivity of in vitro neural glia tissue model modulated through integrative control of matrix stiffness and a neurotrophic factor.

Brain function emerges from intricate cellular communication within neural networks. Both In silico neuronal models and primary neuron cells have revealed that the branching architecture of individual neurons determines the bioelectrical signal propagation pattern and dynamics. However, whether stem cell-differentiated neurons can build functional connectivity regulated by neuronal morphology has yet to be determined. Here, we hypothesized that neurite length, branching, or both factors would regulate the functional connectivity of the stem cell-differentiated neural network. We examined this hypothesis by differentiating mouse cortical neural stem cells (NSCs) on Matrigel substrates with varying storage moduli, both with and without basic fibroblast growth factor (bFGF). Interestingly, with bFGF, Matrigel with a storage modulus (G') of 100 Pa drives NSCs to differentiate into neurons with more dendritic branches, while the gel with G' of 50 Pa led to the development of longer neurites with fewer branches. Notably, branch-rich neural networks exhibited an increased frequency of calcium transients. Using a MATLAB-based analysis pipeline incorporating graph theory, we constructed spatial and temporal calcium activity maps, revealing that branching complexity, more than neurite length, correlates with the density and strength of functional neural circuits. Overall, this study demonstrates that the dendritic branching of neurons, modulated with matrix stiffness and neurotrophic factors, is a key element in enhancing the electrophysiological functionality of the stem cell-differentiated neural network. This finding will have a significant impact on efforts to reconstruct functional neural tissue models, advancing both regenerative therapies and unexplored applications, including biological computing.

Animals↗
PubMed2026

An NFATC4 phospho-switch links matrix stiffness to fibroblast fate.

Fibrosis is driven by the activation of quiescent fibroblasts into contractile, matrix-secreting myofibroblasts, a transition governed jointly by biochemical signals and by the mechanical properties of the ECM. How the physical stiffness of tissue is converted into a durable transcriptional cell fate decision has remained poorly understood. In this issue of the JCI, Kadri et al. used global phosphoproteomic profiling of primary human lung fibroblasts across a defined stiffness gradient to identify phosphorylation of NFATC4 at residues S213/S217 as a mechanosensitive switch that is both necessary and sufficient for the fibroblast-to-myofibroblast transition. They validated these predictions in an independent transcriptomic dataset from patients with idiopathic pulmonary fibrosis, showing that NFATC4 expression increased with disease severity. Prior work has implicated NFATC4 activation in cardiac and hepatic fibrosis, suggesting that this single modification may serve as a convergence point for mechanical and cytokine signals across fibrotic diseases.

Humans↗
PubMed1992

The dramatic influence of loading velocity on the compressive response of articular cartilage.

Experiments were carried out to investigate the influence of loading velocity on the stiffness of the articular cartilage matrix. Compression tests were conducted on cartilage alone and cartilage-on-bone at strain-rates ranging from 10(-5)sec-1 to 10(3)sec-1 and it was established that matrix stiffness increased progressively in the "low" and "medium" strain-rate regimens and assumes a limiting value at "high" rates of loading up to impact. Analysis of the strain field characteristics associated with the compression process, both at low and high velocities, suggests that two fundamentally different mechanisms of deformation control the development of cartilage matrix stiffness. At low strain-rates a consolidation-dependent stiffness occurs while at high strain rates the high stiffness results from a classical elastic deformation process. This bifurcation in the tissue's response to loading is likely to affect the redistribution of joint contact stresses being transmitted into the subchondral bone.

Animals↗
PubMed1990

Fracture behaviour of cartilage-on-bone in response to repeated impact loading.

Cartilage-on-bone composite samples, of differing degrees of matrix stiffness of the cartilage, were subjected to repeated dynamic compression. In all but the most compliant cartilage, fractures always presented at 45 degrees to the articular surface and extended only to the boundary between the intermediate and deep zones of the cartilage matrix. Fractures were not initiated in cartilage of very low matrix stiffness, in which the articular surface and superficial zone are always poorly constructed, nor in high-stiffness cartilage in which the articular surface and superficial zone had been shaved off. It is postulated that an intact superficial layer is necessary for fracture initiation and that propagation of the fracture into the intermediate zone occurs along the planes of maximum resolved shear stress. Prolonged impaction can cause crushing of the underlying subchondral bone, the cartilage remaining structurally and mechanically unchanged. Thus under high rates of loading stress is transmitted to the bone, whilst the cartilage either remains unaffected or fails in a manner characteristic of a brittle material.

Animals↗
PubMed1990

Human arm stiffness characteristics during the maintenance of posture.

When the hand is displaced from an equilibrium position, the muscles generate elastic forces to restore the original posture. In a previous study, Mussa-Ivaldi et al. (1985) have measured and characterized the field of elastic forces associated with hand posture in the horizontal plane. Hand stiffness which describes the relation between force and displacement vectors in the vicinity of equilibrium position was measured and graphically represented by an ellipse, characterized by its size, shape and orientation. The results indicated that the shape and orientation of the stiffness ellipse are strongly dependent on arm configuration. At any given hand position, however, the values of these parameters were found to remain invariant among subjects and over time. In this study we investigate the underlying causes for the observed spatial pattern of variation of the hand stiffness ellipse. Mathematically analyzing the relation between hand and joint stiffness matrices, we found that in order to produce the observed spatial variations of the stiffness ellipse, the shoulder stiffness must covary in the workspace with the stiffness component provided by the two-joint muscles. This condition was found to be satisfied by the measured joint stiffness components. Using anatomical data and considering the effects that muscle cross-sections and changes in muscle moment arms have on the joint stiffness matrix, we found that these anatomical factors are not sufficient to account for the observed pattern of variation of joint stiffness in the workspace. To examine whether the coupling between shoulder and two-joint stiffnesses results from the coactivation of muscles contributing to these stiffnesses, EMG signals were recorded from shoulder, elbow and two-joint muscles. Our results indicated that, while some muscle coactivation may indeed exist, it can be found for only some of the muscles and in only part of the workspace.

Arm↗
PubMed1992

A theoretical model of the knee and ACL: theory and experimental verification.

A three-dimensional mathematical model of the human knee joint was developed to examine the role of single ligaments, such as an anterior cruciate ligament (ACL) graft in ACL reconstruction, on joint motion and tissue forces. The model is linear and valid for small motions about an equilibrium position. The knee joint is modeled as two rigid bodies (the femur and the tibia) interconnected by deformable structures, including the ACL or ACL graft, the cartilage layer, and the remainder of the knee tissues (modeled as a single element). The model was demonstrated for the equilibrium condition of the knee in extension with an anterior tibial force, causing anterior drawer and hyperextension. The knee stiffness matrix for this condition was measured for a human right knee in vitro. Predicted model response was compared with experimental observations. Qualitative agreement was found between model and experiment, validating the model and its assumptions. The model was then used to predict the change in graft and cartilage forces and joint motion of the knee due to an increment of load in the normal joint both after ACL removal and with various altered states simulating ACL reconstructions. Results illustrate the interdependence between loads in the ACL graft, other knee structures, and contact force. Stiffer grafts and smaller maximum unloaded length of the ligament lead to higher graft and contact forces. Changes in cartilage stiffness alter load sharing between ACL graft and other joint tissues.

Anterior Cruciate Ligament↗
PubMed2026

Rewiring Cellular Context as A Central Mechanism Governing Cancer Stem Cell Survival: Insights from ESC Comparisons.

Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance, yet their remarkable persistence remains poorly understood. While CSCs share stemness attributes with embryonic stem cells (ESCs), including self-renewal, transcriptional plasticity, and permissive chromatin, they exhibit a fundamentally divergent regulatory logic that prioritizes survival over developmental fidelity. ESCs maintain globally open chromatin that supports transcriptional hyperactivity but predisposes them to apoptosis under genotoxic stress, whereas CSCs maintain dynamically inducible, permissive chromatin at survival loci while repressing differentiation programs, enabling adaptive stress responses. We advance the hypothesis that CSC persistence emerges not from any single factor, but from the integrative rewiring of signaling cascades (Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR), stress-responsive transcription factors (HIFs, NF-κB, STAT3), and core pluripotency networks (OCT4, SOX2, NANOG) within a survival-centric context, reinforced by dynamic chromatin remodeling, inducible super-enhancer landscapes, and microenvironmental cues (hypoxia, inflammation, matrix stiffness). Within this framework, the E2F family serves as a key contextual integrator: in ESCs, constitutive E2F activity triggers p53-mediated apoptosis upon DNA damage, preserving genomic integrity; in CSCs, deregulated E2F activity redirects transcription toward DNA repair, antioxidant defenses, and anti-apoptotic programs. This functional divergence underscores that phenotypic outcome is determined by the broader cellular and epigenetic landscape rather than any single factor. We conclude that CSC persistence is an emergent property of this integrated, survival-centric program, fundamentally distinct from the developmental imperative of ESCs. Effective therapeutic strategies must therefore move beyond targeting individual pathways to dismantle the interconnected regulatory networks that define the CSC survival context, offering a more robust approach to overcome therapy resistance and prevent tumor relapse.

Cancer Stem Cells (CSCs)↗
PubMed1987

Response of a human head/neck/upper-torso replica to dynamic loading--II. Analytical/numerical model.

A three-dimensional lumped-parameter model of the human head/neck/upper-torso was developed to predict its motion for any specified initial conditions and that could also be used to compare with the results of other investigators. This model consists of ten rigid bodies representing the head, cervical vertebrae C1-C7, T1 and T2 combined with the rest of the torso. These rigid bodies were connected by intervertebral joints described by a stiffness matrix relating the force (moment) and translation (rotation). Fifteen pairs of muscles were incorporated in the model, represented by three-point linear elements with nonlinear constitutive relationships obtained from cadaver test results. The calculated response compared favorably with human volunteer data for both flexion and lateral whiplash. However, tests on an inanimate replica of a human indicated greater flexibility than predicted by the corresponding numerical model. The difference is believed to be due to insufficient mass of the muscles incorporated in the structure.

Acceleration↗
PubMed1992

Application of the finite-element method to simulation of damage to the human skull as a consequence of missile impact on a multi-layered composite crash helmet.

Finite-element analysis is a powerful technique which could be applicable to the study of a wide range of circumstances where the frame and/or the vital organs of the body are subjected to extreme loading conditions. This paper reports the results of an exploratory investigation in which the performance of a crash helmet in protecting the skull from an impacting load is modelled. The immediate objective is to show how a typical crash helmet design of glass-reinforced plastic (GRP) outer casing with quasi-foam-like liner can, with a suitable choice of material properties, attenuate the transfer of energy from the impacting mass such that the damage intensity to the skull is minimized. A simplified structure for both helmet and skull shape is adopted and the skull is modelled as being supported on an elastic foundation. The material properties used are representative rather than being accurately matched to experimentally determined ones. Several aspects of the modelling technique are worthy of particular note: the simulation of material anisotropy by means of multiple reinforcement layers with varying orientation, the use of dashpot elements for energy attenuation and the incorporation of multipoint constraint between the skull and the helmet lining to ensure integrity of the model with correct stiffness matrix values and allowing independent monitoring of all stress levels at the mating interface region. The results of the modelling show that the specific limited objectives can be met but also indicate how vitally important information could be obtained from similar but more detailed studies which included representative modelling of the body organs and skeleton.

Anisotropy↗
PubMed1990

Incorporation of spinal flexibility measurements into finite element analysis.

This technical note demonstrates two methods of incorporating the experimental stiffness of spinal motion segments into a finite element analysis of the spine. The first method is to incorporate the experimental data directly as a stiffness matrix. The second method approximates the experimental data as a beam element.

Elasticity↗
PubMed1990

New design of hip prosthesis using carbon fibre reinforced composite.

We present a new design for a hip prosthesis using polyethylene-hydroxyapatite, a composite material with layered stiffness and good bone compatibility. In order to overcome the low stiffness of the matrix, carbon fibre reinforcement is suggested. This new collarless prosthesis was designed to give maximum stiffness at the core and lower stiffness at the bone-implant interface. For this design a 2D finite element analysis was undertaken; its results were compared with those for a titanium alloy prosthesis. The effect of the variation in the collar stiffness was also analysed.

Carbon↗
PubMed1988

Composition of the cement line and its possible mechanical role as a local interface in human compact bone.

Human compact bone may be viewed as a fiber reinforced composite material in which the secondary osteons act as the fiber reinforcements. The cement line, which is the interface between the 'fibers' (osteons) and extraosteonal bone matrix, may impart important mechanical properties to compact bone. The nature of these properties is not known partly because the composition of the cement line is unknown. This analysis examines the constituents of the osteon cement line using scanning electron microscopy and X-ray microprobe analysis to address its biomechanical functions as a local interface. The analysis suggests that the cement line is a region of reduced mineralization which may contain sulfated mucosubstances. This composition is consistent with the hypothesis that the cement line provides a relatively ductile interface with surrounding bone matrix, and that it provides the point specific stiffness differences, poor 'fiber'-matrix bonding and energy transfer qualities required to promote crack initiation but slow crack growth in compact bone.

Adult↗
PubMed1992

Cracks emanating from slipping inclusions near a bone-implant interface.

It has been hypothesized that mechanical fracture at the bone-cement-implant interface is the initial cause for loosening of orthopedic implants. Previous investigators have observed cracks to emanate from methacrylate beads, apparently acting as inclusions within the cement. It is believed that the bond between these inclusions and the surrounding matrix breaks prior to emanation of radial cracks from the inclusion. An analytical model is developed for radial cracks emanating from circular inclusions that allow slip along their interface. The solution to the interaction of a single dislocation and a slipping inclusion is used as a Green's Function to model the crack. The Mode I stress intensity factors are calculated for arbitrary orientations of the crack and for varying relative stiffness of the matrix and the inclusion to test feasibility of crack growth.

Bone Cements↗
PubMed1991

Diastolic function in coronary artery disease.

Diastolic function in coronary artery disease is modified to a variable extent. There are distinct abnormalities produced during acute ischemia, and following myocardial infarction. The pathophysiology of diastolic abnormalities in these two syndromes is reviewed. During acute ischemia filling pressures of the left ventricle are increased. Pulmonary edema may be produced. Silent ischemia causes less of an increase in filling pressures. The diastolic pressure-volume relation is shifted in an upward manner with a variable contribution from altered myocardial relaxation, increased muscle stiffness, acute pericardial restriction, ventricular interaction, and acute chamber dilatation. The impairment of myocardial relaxation plays a central role and has been quantified in multiple clinical and experimental studies. Filling of the left ventricle during ischemia is altered due to the factors which shift the pressure-volume relation. The acute increase in left atrial pressure may increase filling rates somewhat surprisingly, given the reduced left ventricular compliance. Myocardial fibrosis following infarction may elevate filling pressures, but the degree of elevation is closely tied to the intravascular volume status. Shifts in the diastolic pressure-volume relation reflect a loss of chamber compliance due to an increase in muscle stiffness. Increased amounts of extracellular matrix, specifically collagen, produce this permanent increase in muscle stiffness which is central to the diastolic abnormalities in chronic coronary artery disease.

Angina Pectoris↗
PubMed1988

A biomechanical profile across the patellar groove articular cartilage: implications for defining matrix health.

Macroscopically normal articular cartilage across all bovine patellar grooves studied exhibited a smooth gradation in mechanical properties. Rigorous standardisation of microtensile and microcompressive testing showed that stiffness in tension of the deep matrix, its tendency to rupture and compressive stiffness all dropped progressively across the medial margin and trough of the groove, and reached their lowest values at approximately one quarter of the distance up the lateral margin. The changes in mechanical properties were correlated with ultrastructural differences. The deep matrix of very stiff tissue from the medial margin showed a dense arrangement of fibril segments orientated with varying degrees of obliquity about a radial mean. The more compliant tissue had a markedly less dense fibrillar array with a pronounced radial orientation. It is suggested that the gradation in mechanical properties results from differential loading of the joint surface. From the available evidence it seems likely that the compliance of the cartilage increases proportionately with the reduction in load. The results are discussed with reference to Broom's (1986b) model of the fibrillar architecture of cartilage. It is proposed that increasing compliance is related to a graduated reduction across the joint surface in the number and/or strength of the interfibrillar bonds, resulting from differential loading. A proportionate number of fibrils would have a reduced number of short-period lateral deflections and thus an increasingly overall radial orientation. This would result in a concomitant graded reduction in the degree of constraint exerted by the three dimensional fibrillar network on the hydrated proteoglycans.

Animals↗