Matrix stiffness modulates inhibition of HCV replication by Fluvastatin in vitro

2013 ◽  
Vol 51 (01) ◽  
Author(s):  
J Kah ◽  
J Schrader ◽  
A Wüstenberg ◽  
G Tiegs ◽  
G Sass
Keyword(s):  
Matrix Stiffness

The Effects of Geometry and Static Boundary Conditions on Microvessel Outgrowth in a 3D Model of Angiogenesis

2010 ◽  
Author(s):  
Clayton J. Underwood ◽  
Laxminarayanan Krishnan ◽  
Lowell T. Edgar ◽  
Steve Maas ◽  
James B. Hoying ◽  
...  
Keyword(s):  
Boundary Condition ◽  
Boundary Conditions ◽  
Direct Relationship ◽  
3D Model ◽  
Mechanical Strain ◽  
Matrix Stiffness ◽  
Collagen Gels ◽  
3D Collagen ◽  
In Vitro Angiogenesis

We reported previously that, in addition to mechanical strain, a constrained boundary condition alone can alter the organization of microvessel outgrowth during in vitro angiogenesis [1]. After 6 days of culture in vitro, microvessels aligned parallel to the long axis of rectangular 3D collagen gels that had constrained edges on the ends. However, unconstrained cultures did not show any alignment of microvessels. The ability to direct microvessel outgrowth during angiogenesis has significant implications for engineering prevascularized grafts and tissues in vitro, therefore an understanding of this process is important. Since there is direct relationship between the ability of endothelial cells to contract 3D gels and matrix stiffness [2], we hypothesize that some constrained boundary conditions will increase the apparent matrix stiffness and in turn will limit gel contraction, prevent microvessel alignment, and reduce microvessel outgrowth. The objective of this study was to compare microvessel growth and alignment under several different static boundary conditions.

Dynamic extracellular matrix stiffening induces a phenotypic transformation and a migratory shift in epithelial cells

2020 ◽  
Vol 12 (6) ◽  
pp. 161-174
Author(s):  
Shane C Allen ◽  
Jessica A Widman ◽  
Anisha Datta ◽  
Laura J Suggs
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Soft Tissue Tumors ◽  
Tumor Formation ◽  
Matrix Stiffness ◽  
Mesenchymal Transition ◽  
Cell Clusters

Abstract Soft tissue tumors, including breast cancer, become stiffer throughout disease progression. This increase in stiffness has been shown to correlate to malignant phenotype and epithelial-to-mesenchymal transition (EMT) in vitro. Unlike current models, utilizing static increases in matrix stiffness, our group has previously created a system that allows for dynamic stiffening of an alginate–matrigel composite hydrogel to mirror the native dynamic process. Here, we utilize this system to evaluate the role of matrix stiffness on EMT and metastasis both in vitro and in vivo. Epithelial cells were seen to lose normal morphology and become protrusive and migratory after stiffening. This shift corresponded to a loss of epithelial markers and gain of mesenchymal markers in both the cell clusters and migrated cells. Furthermore, stiffening in a murine model reduced tumor burden and increased migratory behavior prior to tumor formation. Inhibition of FAK and PI3K in vitro abrogated the morphologic and migratory transformation of epithelial cell clusters. This work demonstrates the key role extracellular matrix stiffening has in tumor progression through integrin signaling and, in particular, its ability to drive EMT-related changes and metastasis.

scholarly journals Matrix stiffening promotes a tumor vasculature phenotype

2016 ◽  
Vol 114 (3) ◽  
pp. 492-497 ◽  
Author(s):  
Francois Bordeleau ◽  
Brooke N. Mason ◽  
Emmanuel Macklin Lollis ◽  
Michael Mazzola ◽  
Matthew R. Zanotelli ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Tumor Tissue ◽  
Tumor Vasculature ◽  
Matrix Stiffness ◽  
Matrix Density ◽  
Vessel Structure ◽  
Vessel Growth

Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell–cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.

Extracellular Matrix Stiffness Modulates Microvascular Morphology During Early Sprouting Angiogenesis In Vitro

2009 ◽  
Author(s):  
Laxminarayanan Krishnan ◽  
Urs Utzinger ◽  
Steve Maas ◽  
Shawn Reese ◽  
Jeffrey A. Weiss ◽  
...  
Keyword(s):  
Matrix Stiffness ◽  
Matrix Rigidity ◽  
Cellular Functions ◽  
Sprouting Angiogenesis ◽  
Vascular Morphology ◽  
The Matrix ◽  
Extracellular Matrix Stiffness ◽  
Local Stiffness ◽  
Matrix Orientation

Sprouting angiogenesis is associated with changes in matrix stiffness[1]. Neovessel growth and morphology are in turn affected by the changes in matrix orientation or forces acting on the matrix[2]. Matrix rigidity influences the formation of cord like structures[3, 4] and could play a role in development of tissue specific vascular morphology or inhibit cellular functions in diseases. The effect of matrix stiffness on neovessel growth from preformed vasculature has not been examined. Matrix stiffness could be increased both by an increase in matrix density[5] as well as increased crosslink formation, as in hyperglycemia[6]. It is thus essential to first identify the effect of increase in local stiffness alone, in the absence of artificially induced crosslinks, which may interfere with matrix orientation. Our aim is to characterize changes in early angiogenesis associated with ECM of different densities and relate these to changes in matrix orientation.

scholarly journals Sustained mechanical tension governs fibrogenic activation of tendon stromal cells in systemic sclerosis

2021 ◽  
Author(s):  
Amro A. Hussien ◽  
Robert Knell ◽  
Florian Renoux ◽  
Stefania Wunderli ◽  
Barbara Niederoest ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Tissue Mechanics ◽  
Matrix Stiffness ◽  
Stromal Fibroblasts ◽  
3D Matrix ◽  
Clinical Models ◽  
Function Relationship ◽  
Activated Fibroblasts ◽  
Tissue Models

Fibrosis is a pathological outcome of aberrant repair responses in systemic sclerosis and affects many tissues, including tendons. Progressive matrix stiffening is a key feature of this pathological remodeling. How dysregulated tissue mechanics contribute to the persistence of the fibrotic phenotype has been obscured by limited availability of experimental tissue models that are both controllable and capture essential aspects of the tendon biophysical niche. Here, we developed a modular, cantilever-based platform that allows culture of 3D tendon-like constructs under easily variable static tension, emulating this central tendon-specific structure function relationship. The system reveals that elevated matrix tension instigates fibroblast-to-myofibroblast activation eliciting scar-like phenotypes in vitro. By using this mechano-culture system and preclinical and clinical models of systemic sclerosis, we further show that 3D matrix stiffness is inversely correlated with the transcription of major pro-fibrotic collagens, but positively correlate with the expression of markers of stromal-immune interactions. Co-culture of tendon stromal fibroblasts and bone marrow-derived macrophages override stiffness-mediated downregulation of matrix transcription, suggesting that normal tension mediated checkpoints are superseded by the local tissue immune state. Our study highlights the power of 3D reductionist approaches in dissecting the contribution of the elevated matrix tension to the positive feedforward loops between activated fibroblasts and progressive ECM stiffening in systemic sclerosis.

Calcific Nodule Morphogenesis by Aortic Valve Interstitial Cells: Synergism of Applied Strain and TGF-β1

2011 ◽  
Author(s):  
Joseph Chen ◽  
Charles I. Fisher ◽  
M. K. Sewell-Loftin ◽  
W. David Merryman
Keyword(s):  
Aortic Valve ◽  
The United States ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Matrix Stiffness ◽  
Calcific Aortic Valve Disease ◽  
Valve Interstitial Cells ◽  
Compliant Substrates ◽  
Tgf Β1

Calcific Aortic Valve Disease (CAVD) is the third most common cause of cardiovascular disease, affecting nearly 5 million people in the United States alone. It is now the most common form of acquired valvular disease in industrialized countries and will likely affect more individuals in the coming years as the prevalence increases with life expectancy. It is known that the progression of CAVD is closely related to the behavior of aortic valve interstitial cells (AVICs); however the cellular mechanobiological mechanisms leading to dysfunction remain unclear. Generally, CAVD is characterized by the formation of calcified AVIC aggregates with an apoptotic core. These aggregates increase the leaflet stiffness and impede normal valve function. Multiple studies have investigated the effects of various biochemical cues on this process, such as transformation growth factor β1 (TGF-β1), on the regulation of nodule formation [1]. Additionally, Yip et al revealed that matrix stiffness controls nodule formation in vitro, with stiffer substrates promoting apoptotic nodule formation, while compliant substrates generated nodules containing cells with osteoblast markers [2]. This suggests that matrix stiffness is involved in the regulatory mechanisms of nodule formation and may initiate different types of nodule formation (i.e. osteogenic vs. dystrophic). In the current study, we examined the synergistic role of strain and TGF-β1 in the generation of calcified nodules AVICs.

scholarly journals Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Yinying Dong ◽  
Qiongdan Zheng ◽  
Zhiming Wang ◽  
Xiahui Lin ◽  
Yang You ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Epithelial Mesenchymal Transition ◽  
Liver Stiffness ◽  
Pathological Process ◽  
Matrix Stiffness ◽  
Invasion And Metastasis ◽  
Snail Expression ◽  
Mesenchymal Transition ◽  
Hcc Cells

Abstract Background Increased liver stiffness exerts a detrimental role in driving hepatocellular carcinoma (HCC) malignancy and progression, and indicates a high risk of unfavorable outcomes. However, it remains largely unknown how liver matrix stiffness as an independent cue triggers epithelial-mesenchymal transition (EMT) and facilitates HCC metastasis. Methods Buffalo rat HCC models with different liver stiffness backgrounds and an in vitro Col I-coated cell culture system with tunable stiffness were used in the study to explore the effects of matrix stiffness on EMT occurrence and its underlying molecular mechanism. Clinical significance of liver stiffness and key molecules required for stiffness-induced EMT were validated in HCC cohorts with different liver stiffness. Results HCC xenografts grown in higher stiffness liver exhibited worse malignant phenotypes and higher lung metastasis rate, suggesting that higher liver stiffness promotes HCC invasion and metastasis. Cell tests in vitro showed that higher matrix stiffness was able to strikingly strengthen malignant phenotypes and independently induce EMT occurrence in HCC cells, and three signaling pathways converging on Snail expression participated in stiffness-mediated effect on EMT including integrin-mediated S100A11 membrane translocation, eIF4E phosphorylation, and TGF β1 autocrine. Additionally, the key molecules required for stiffness-induced EMT were highly expressed in tumor tissues of HCC patients with higher liver stiffness and correlated with poor tumor differentiation and higher recurrence. Conclusions Higher matrix stiffness as an initiator triggers epithelial-mesenchymal transition (EMT) in HCC cells independently, and three signaling pathways converging on Snail expression contribute to this pathological process. This work highlights a significant role of biomechanical signal in triggering EMT and facilitating HCC invasion and metastasis.

scholarly journals TRPV4 Plays a Role in Matrix Stiffness-Induced Macrophage Polarization

2020 ◽  
Vol 11 ◽  
Author(s):  
Bidisha Dutta ◽  
Rishov Goswami ◽  
Shaik O. Rahaman
Keyword(s):  
Transient Receptor Potential ◽  
Macrophage Polarization ◽  
Transient Receptor Potential Vanilloid ◽  
Polarization Spectrum ◽  
Dependent Manner ◽  
Matrix Stiffness ◽  
Soft Matrix ◽  
Genetic Ablation ◽  
M1 Macrophage

Phenotypic polarization of macrophages is deemed essential in innate immunity and various pathophysiological conditions. We have now determined key aspects of the molecular mechanism by which mechanical cues regulate macrophage polarization. We show that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechanosensitive ion channel, mediates substrate stiffness-induced macrophage polarization. Using atomic force microscopy, we showed that genetic ablation of TRPV4 function abrogated fibrosis-induced matrix stiffness generation in skin tissues. We have determined that stiffer skin tissue promotes the M1 macrophage subtype in a TRPV4-dependent manner; soft tissue does not. These findings were further validated by our in vitro results which showed that stiff matrix (50 kPa) alone increased expression of macrophage M1 markers in a TRPV4-dependent manner, and this response was further augmented by the addition of soluble factors; neither of which occurred with soft matrix (1 kPa). A direct requirement for TRPV4 in M1 macrophage polarization spectrum in response to increased stiffness was evident from results of gain-of-function assays, where reintroduction of TRPV4 significantly upregulated the expression of M1 markers in TRPV4 KO macrophages. Together, these data provide new insights regarding the role of TRPV4 in matrix stiffness-induced macrophage polarization spectrum that may be explored in tissue engineering and regenerative medicine and targeted therapeutics.

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