scholarly journals The Extracellular Matrix Contributes to Mechanotransduction in Uterine Fibroids

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Phyllis C. Leppert ◽  
Friederike L. Jayes ◽  
James H. Segars
Keyword(s):  
Extracellular Matrix ◽  
Critical Role ◽  
Uterine Fibroids ◽  
Common Disease ◽  
Mechanical Forces ◽  
Chemical Signaling ◽  
Signaling System ◽  
New Strategies ◽  
Fibroid Growth

The role of the extracellular matrix (ECM) and mechanotransduction as an important signaling factor in the human uterus is just beginning to be appreciated. The ECM is not only the substance that surrounds cells, but ECM stiffness will either compress cells or stretch them resulting in signals converted into chemical changes within the cell, depending on the amount of collagen, cross-linking, and hydration, as well as other ECM components. In this review we present evidence that the stiffness of fibroid tissue has a direct effect on the growth of the tumor through the induction of fibrosis. Fibrosis has two characteristics: (1) resistance to apoptosis leading to the persistence of cells and (2) secretion of collagen and other components of the ECM such a proteoglycans by those cells leading to abundant disposition of highly cross-linked, disoriented, and often widely dispersed collagen fibrils. Fibrosis affects cell growth by mechanotransduction, the dynamic signaling system whereby mechanical forces initiate chemical signaling in cells. Data indicate that the structurally disordered and abnormally formed ECM of uterine fibroids contributes to fibroid formation and growth. An appreciation of the critical role of ECM stiffness to fibroid growth may lead to new strategies for treatment of this common disease.

Mechanical Signaling and Extracellular Matrix in Uterine Fibroids

2017 ◽  
Vol 35 (06) ◽  
pp. 487-493 ◽  
Author(s):  
Saima Rafique ◽  
James Segars ◽  
Phyllis Leppert
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Reproductive Tract ◽  
Critical Role ◽  
Uterine Fibroids ◽  
Female Reproductive Tract ◽  
Benign Tumors ◽  
Mechanical Signaling ◽  
Abnormal Cells ◽  
Fibroid Growth

AbstractFibroids (uterine leiomyomas) are the most common benign tumors of the female reproductive tract. Steroid hormones, growth factors, and cytokines have long been implicated in fibroid growth; however, research suggests that changes in the extracellular matrix and mechanical signaling play a critical role in fibroid growth and differentiation. Studies have shown that growth of fibroids is related to the change in the volume and composition of extracellular matrix with increased deposition of abnormal collagen, glycoproteins, laminins, fibronectins, and an increased osmotic stress. These changes generate mechanical stress which is converted to chemical signals in the cells through mechanotransduction and eventually affects gene expression and protein synthesis. Current studies also suggest that mechanical signaling in fibroid cells is abnormal as evidenced by decreased apoptosis of abnormal cells and deposition of a stiff extracellular matrix promoting fibrosis. Understanding and defining these mechanisms could help design new therapies for the treatment of fibroids.

scholarly journals Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 409 ◽  
Author(s):  
Manuela Antoniel ◽  
Francesco Traina ◽  
Luciano Merlini ◽  
Davide Andrenacci ◽  
Domenico Tigani ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Critical Role ◽  
Active Form ◽  
Congenital Muscular Dystrophy ◽  
Cell Polarization ◽  
Pcr Analysis ◽  
Matrix Remodeling ◽  
Collagen Vi

Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients.

The role of the physicochemical environment in determining disc cell behaviour

2002 ◽  
Vol 30 (6) ◽  
pp. 858-863 ◽  
Author(s):  
J. P. G. Urban
Keyword(s):  
Extracellular Matrix ◽  
Ionic Composition ◽  
Cell Types ◽  
Mechanical Forces ◽  
Dense Matrix ◽  
Cellular Activity ◽  
High Concentration ◽  
Cell Behaviour ◽  
Disc Cells

The cells of the intervertebral disc exist in an unusual environment. They are embedded in a dense matrix containing a high concentration of aggrecan whose fixed negative charges regulate the extracellular ionic composition and osmolarity; both extracellular cation concentrations and osmolarity are considerably higher than those experienced by most cell types. The disc also is avascular. Oxygen levels in the centre of the nucleus, where cells may be 6–8 mm from the blood supply, are very low. Since metabolism is mainly by glycolysis, lactic acid is produced at high rates and hence the pH is acidic. Finally, the disc is subjected to mechanical forces at all times; these vary with posture and activity. In particular, because the disc is under low loads during rest and high loads during the day's activities, it loses and regains around 25% of its fluid over a diurnal cycle with consequent changes to the concentrations of extracellular matrix macromolecules and ions and hence extracellular osmolality. Here we will briefly review these factors and discuss the influence of changes in the physicochemical environment on cellular activity, in particular on the rate at which disc cells synthesize and degrade matrix macro-molecules.

scholarly journals Different DNA methylome, transcriptome and histological features in uterine fibroids with and without MED12 mutations

2021 ◽  
Author(s):  
Ryo Maekawa ◽  
Shun Sato ◽  
Tetsuro Tamehisa ◽  
Takahiro Sakai ◽  
Takuya Kajimura ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Blood Vessels ◽  
Uterine Fibroids ◽  
Muscle Cells ◽  
Histological Features ◽  
Dna Methylome

Abstract Background: Somatic mutations in Mediator complex subunit 12 (MED12m) have been reported as a biomarker of uterine fibroids (UFs). However, the role of MED12m is still unclear in the pathogenesis of UFs. Therefore, we investigated the differences in DNA methylome, transcriptome, and histological features between MED12m-positive and -negative UFs. Methods: DNA methylomes and transcriptomes were obtained from MED12m-positive and -negative UFs and myometrium, and hierarchically clustered. Differentially expressed genes in comparison with the myometrium and co-expressed genes detected by weighted gene co-expression network analysis were subjected to gene ontology enrichment analyses. The amounts of collagen fibers and the number of blood vessels and smooth muscle cells were histologically evaluated. Results: Hierarchical clustering based on DNA methylation clearly separated the myometrium, MED12m-positive, and MED12m-negative UFs. MED12m-positive UFs had the increased activities of extracellular matrix formation, whereas MED12m-negative UFs had the increased angiogenic activities and smooth muscle cell proliferation. Conclusion: The MED12m-positive and -negative UFs had different DNA methylation, gene expression, and histological features. The MED12m-positive UFs form the tumor with a rich extracellular matrix and poor blood vessels and smooth muscle cells compared to the MED12m-negative UFs, suggesting MED12 mutations affect the tissue composition of UFs.

scholarly journals Endothelial cell polarity and extracellular matrix production rely on functional ATP6AP2 during developmental and pathological angiogenesis

2021 ◽  
Author(s):  
NR Patel ◽  
A Blanks ◽  
Y Li ◽  
MC Prieto ◽  
SM Meadows
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Cell Polarity ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Matrix Composition ◽  
Pathological Angiogenesis ◽  
Extracellular Matrix Components

AbstractThe (Pro)renin receptor ((P)RR), also known as ATP6AP2, is a single-transmembrane protein that is implicated in a multitude of biological processes. However, the exact role of ATP6AP2 during blood vessel development remains largely undefined. Here, we use an inducible endothelial cell (EC)-specific Atp6ap2 knockout mouse model to investigate the role of ATP6AP2 during both physiological and pathological angiogenesis in vivo. We observed that postnatal deletion of Atp6ap2 in ECs results in cell migration defects, loss of tip cell polarity and subsequent impairment of retinal angiogenesis. In vitro, Atp6ap2 deficient ECs similarly displayed reduced cell migration, impaired sprouting, and defective cell polarity. Transcriptional profiling of ECs isolated from Atp6ap2 mutant mice further indicated regulatory roles in angiogenesis, cell migration and extracellular matrix composition. Mechanistically, we showed that expression of various extracellular matrix components is controlled by ATP6AP2 via the extracellular-signal-regulated kinase (ERK) pathway. Furthermore, Atp6ap2 deficient retinas exhibited reduced revascularization in an oxygen induced retinopathy model. Collectively, our results demonstrated a critical role of ATP6AP2 as a regulator of developmental and pathological angiogenesis.

scholarly journals Vascular dysfunction and pathology: focus on mechanical forces

2021 ◽  
Author(s):  
Gloria Garoffolo ◽  
Maurizio Pesce
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Cardiovascular System ◽  
Vascular Dysfunction ◽  
Force Distribution ◽  
Mechanical Forces ◽  
Biophysical Properties ◽  
Epigenetic Programming ◽  
New Concepts

The role of mechanical forces is emerging as a new player in pathophysiologic programming of the cardiovascular system. The ability of the cells to ‘sense’ mechanical forces does not relate only to perception of movement or flow, as intended traditionally, but also to the biophysical properties of the extracellular matrix, the geometry of the tissues and the force distribution inside them. This is also supported by the finding that cells can actively translate mechanical cues into discrete gene expression and epigenetic programming. In the present review we will contextualize these new concepts in the vascular pathologic programming.

The Role of Cardiac Fibroblasts in Extracellular Matrix-Mediated Signaling During Normal and Pathological Cardiac Development

2013 ◽  
Vol 135 (7) ◽  
Author(s):  
Kelly Elizabeth Sullivan ◽  
Lauren Deems Black
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Heart Defects ◽  
Critical Role ◽  
Heart Tissue ◽  
Physical And Chemical

The extracellular matrix is no longer considered a static support structure for cells but a dynamic signaling network with the power to influence cell, tissue, and whole organ physiology. In the myocardium, cardiac fibroblasts are the primary cell type responsible for the synthesis, deposition, and degradation of matrix proteins, and they therefore play a critical role in the development and maintenance of functional heart tissue. This review will summarize the extensive research conducted in vivo and in vitro, demonstrating the influence of both physical and chemical stimuli on cardiac fibroblasts and how these interactions impact both the extracellular matrix and, by extension, cardiomyocytes. This work is of considerable significance, given that cardiovascular diseases are marked by extensive remodeling of the extracellular matrix, which ultimately impairs the functional capacity of the heart. We seek to summarize the unique role of cardiac fibroblasts in normal cardiac development and the most prevalent cardiac pathologies, including congenital heart defects, hypertension, hypertrophy, and the remodeled heart following myocardial infarction. We will conclude by identifying existing holes in the research that, if answered, have the potential to dramatically improve current therapeutic strategies for the repair and regeneration of damaged myocardium via mechanotransductive signaling.

scholarly journals The critical role of the cellular thiol homeostasis in cadmium perturbation of the lung extracellular matrix

Toxicology ◽  
2010 ◽  
Vol 267 (1-3) ◽  
pp. 60-69 ◽  
Author(s):  
Yinzhi Zhao ◽  
Lijun Chen ◽  
Song Gao ◽  
Paul Toselli ◽  
Phillip Stone ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Critical Role ◽  
Thiol Homeostasis ◽  
Cellular Thiol

scholarly journals Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Miaoqin Chen ◽  
Shiman Hu ◽  
Yiling Li ◽  
Ting Ting Jiang ◽  
Hongchuan Jin ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Tumor Control ◽  
New Strategies

AbstractCancer immunotherapy especially immune checkpoint inhibition has achieved unprecedented successes in cancer treatment. However, there are many patients who failed to benefit from these therapies, highlighting the need for new combinations to increase the clinical efficacy of immune checkpoint inhibitors. In this review, we summarized the latest discoveries on the combination of nucleic acid-sensing immunity and immune checkpoint inhibitors in cancer immunotherapy. Given the critical role of nuclear acid-mediated immunity in maintaining the activation of T cell function, it seems that harnessing the nuclear acid-mediated immunity opens up new strategies to enhance the effect of immune checkpoint inhibitors for tumor control.

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