scholarly journals Mechanism of Mechanical Trauma-Induced Extracellular Matrix Remodeling of Fibroblasts in Association with Nrf2/ARE Signaling Suppression Mediating TGF-β1/Smad3 Signaling Inhibition

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Jianming Tang ◽  
Bingshu Li ◽  
Cheng Liu ◽  
Yang Li ◽  
Qiannan Li ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Oxidative Damage ◽  
Nuclear Translocation ◽  
Mechanical Strain ◽  
Mechanical Injury ◽  
Mechanical Trauma ◽  
Matrix Remodeling ◽  
Ecm Remodeling

Stress urinary incontinence (SUI) is a common hygienic problem affecting the quality of women’s life worldwide. In this research, we revealed the involvement and regulation of extracellular matrix (ECM) remodeling, oxidative damage, and TGF-β1 signaling in the pathological mechanisms of mechanical trauma-induced SUI. We found that excessive mechanical strain significantly increased apoptosis rate, decreased cell viability and ECM production, and broke the balance of MMPs/TIMPs compared with the nonstrain control (NC) group. The expression levels of TGFβ1, p-Smad3, Nrf2, GPx1, and CAT were downregulated, the production of ROS, 8-OHdG, 4-HNE, and MDA was increased, and the nuclear translocation of Smad2/3 was suppressed after 5333 μstrain’s treatment. Both mTGF-β1 pretreatment and Nrf2 overexpression could reverse mechanical injury-induced TGFβ1/Smad3 signaling inhibition and ECM remodeling, whereas mTGF-β1 had no effect on Nrf2 expression. Nrf2 overexpression significantly alleviated mechanical injury-induced ROS accumulation and oxidative damage; in contrast, Nrf2 silencing exhibited opposite effects. Besides, vaginal distention- (VD-) induced in vivo SUI model was used to confirm the in vitro results; Nrf2 knockout aggravates mechanical trauma-induced LPP reduction, ECM remodeling, oxidative damage, and TGF-β1/Smad3 suppression in mice. Therefore, we deduce that mechanical injury-induced ECM remodeling might be associated with Nrf2/ARE signaling suppression mediating TGF-β1/Smad3 signaling inhibition. This might reflect a new molecular target for SUI researches.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling

2018 ◽  
Vol 315 (4) ◽  
pp. H771-H789 ◽  
Author(s):  
Nethika R. Ariyasinghe ◽  
Davi M. Lyra-Leite ◽  
Megan L. McCain
Keyword(s):  
Cardiovascular Disease ◽  
Extracellular Matrix ◽  
Myocardial Function ◽  
Myocardial Cell ◽  
Three Dimensions ◽  
Model Systems ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Microphysiological Systems

Many cardiovascular diseases are associated with pathological remodeling of the extracellular matrix (ECM) in the myocardium. ECM remodeling is a complex, multifactorial process that often contributes to declines in myocardial function and progression toward heart failure. However, the direct effects of the many forms of ECM remodeling on myocardial cell and tissue function remain elusive, in part because conventional model systems used to investigate these relationships lack robust experimental control over the ECM. To address these shortcomings, microphysiological systems are now being developed and implemented to establish direct relationships between distinct features in the ECM and myocardial function with unprecedented control and resolution in vitro. In this review, we will first highlight the most prominent characteristics of ECM remodeling in cardiovascular disease and describe how these features can be mimicked with synthetic and natural biomaterials that offer independent control over multiple ECM-related parameters, such as rigidity and composition. We will then detail innovative microfabrication techniques that enable precise regulation of cellular architecture in two and three dimensions. We will also describe new approaches for quantifying multiple aspects of myocardial function in vitro, such as contractility, action potential propagation, and metabolism. Together, these collective technologies implemented as cardiac microphysiological systems will continue to uncover important relationships between pathological ECM remodeling and myocardial cell and tissue function, leading to new fundamental insights into cardiovascular disease, improved human disease models, and novel therapeutic approaches.

scholarly journals Airway Epithelial Cell Migration Dynamics: MMP-9 Role in Cell–Extracellular Matrix Remodeling

1999 ◽  
Vol 146 (2) ◽  
pp. 517-529 ◽  
Author(s):  
Claire Legrand ◽  
Christine Gilles ◽  
Jean-Marie Zahm ◽  
Myriam Polette ◽  
Anne-Cécile Buisson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Leading Edge ◽  
Collagen Iv ◽  
Matrix Remodeling ◽  
Airway Epithelial ◽  
Type Iv ◽  
Migration Dynamics

Cell spreading and migration associated with the expression of the 92-kD gelatinase (matrix metalloproteinase 9 or MMP-9) are important mechanisms involved in the repair of the respiratory epithelium. We investigated the location of MMP-9 and its potential role in migrating human bronchial epithelial cells (HBEC). In vivo and in vitro, MMP-9 accumulated in migrating HBEC located at the leading edge of a wound and MMP-9 expression paralleled cell migration speed. MMP-9 accumulated through an actin-dependent pathway in the advancing lamellipodia of migrating cells and was subsequently found active in the extracellular matrix (ECM). Lamellipodia became anchored through primordial contacts established with type IV collagen. MMP-9 became amassed behind collagen IV where there were fewer cell–ECM contacts. Both collagen IV and MMP-9 were involved in cell migration because when cell–collagen IV interaction was blocked, cells spread slightly but did not migrate; and when MMP-9 activation was prevented, cells remained fixed on primordial contacts and did not advance at all. These observations suggest that MMP-9 controls the migration of repairing HBEC by remodeling the provisional ECM implicated in primordial contacts.

scholarly journals Mechanobiology of Epithelia From the Perspective of Extracellular Matrix Heterogeneity

2020 ◽  
Vol 8 ◽  
Author(s):  
Aleksandra N. Kozyrina ◽  
Teodora Piskova ◽  
Jacopo Di Russo
Keyword(s):  
Extracellular Matrix ◽  
Three Dimensional ◽  
Cell Sheets ◽  
Ecm Remodeling ◽  
Cellular Behavior ◽  
New Concepts ◽  
Matrix Heterogeneity ◽  
The Impact

Understanding the complexity of the extracellular matrix (ECM) and its variability is a necessary step on the way to engineering functional (bio)materials that serve their respective purposes while relying on cell adhesion. Upon adhesion, cells receive messages which contain both biochemical and mechanical information. The main focus of mechanobiology lies in investigating the role of this mechanical coordination in regulating cellular behavior. In recent years, this focus has been additionally shifted toward cell collectives and the understanding of their behavior as a whole mechanical continuum. Collective cell phenomena very much apply to epithelia which are either simple cell-sheets or more complex three-dimensional structures. Researchers have been mostly using the organization of monolayers to observe their collective behavior in well-defined experimental setups in vitro. Nevertheless, recent studies have also reported the impact of ECM remodeling on epithelial morphogenesis in vivo. These new concepts, combined with the knowledge of ECM biochemical complexity are of key importance for engineering new interactive materials to support both epithelial remodeling and homeostasis. In this review, we summarize the structure and heterogeneity of the ECM before discussing its impact on the epithelial mechanobiology.

scholarly journals The role of extracellular matrix in normal and pathological pregnancy: Future applications of microphysiological systems in reproductive medicine

2020 ◽  
Vol 245 (13) ◽  
pp. 1163-1174
Author(s):  
Blakely B O’Connor ◽  
Benjamin D Pope ◽  
Michael M Peters ◽  
Carrie Ris-Stalpers ◽  
Kevin K Parker
Keyword(s):  
Extracellular Matrix ◽  
Cellular Adhesion ◽  
Migration And Invasion ◽  
Matrix Remodeling ◽  
Healthy Pregnancy ◽  
Microphysiological Systems ◽  
Maternal Fetal Interface

Remodeling of extracellular matrix in the womb facilitates the dramatic morphogenesis of maternal and placental tissues necessary to support fetal development. In addition to providing a scaffold to support tissue structure, extracellular matrix influences pregnancy outcomes by facilitating communication between cells and their microenvironment to regulate cellular adhesion, migration, and invasion. By reviewing the functions of extracellular matrix during key developmental milestones, including fertilization, embryo implantation, placental invasion, uterine growth, and labor, we illustrate the importance of extracellular matrix during healthy pregnancy and development. We also discuss how maladaptive matrix expression contributes to infertility and obstetric diseases such as implantation failure, preeclampsia, placenta accreta, and preterm birth. Recently, advances in engineering the biotic–abiotic interface have potentiated the development of microphysiological systems, known as organs-on-chips, to represent human physiological and pathophysiological conditions in vitro. These technologies may offer new opportunities to study human fertility and provide a more granular understanding of the role of adaptive and maladaptive remodeling of the extracellular matrix during pregnancy. Impact statement Extracellular matrix in the womb regulates the initiation, progression, and completion of a healthy pregnancy. The composition and physical properties of extracellular matrix in the uterus and at the maternal–fetal interface are remodeled at each gestational stage, while maladaptive matrix remodeling results in obstetric disease. As in vitro models of uterine and placental tissues, including micro-and milli-scale versions of these organs on chips, are developed to overcome the inherent limitations of studying human development in vivo, we can isolate the influence of cellular and extracellular components in healthy and pathological pregnancies. By understanding and recreating key aspects of the extracellular microenvironment at the maternal–fetal interface, we can engineer microphysiological systems to improve assisted reproduction, obstetric disease treatment, and prenatal drug safety.

scholarly journals Extracellular Matrix and Fibrocyte Accumulation in BALB/c Mouse Lung upon Transient Overexpression of Oncostatin M

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 126 ◽  
Author(s):  
Fernando M. Botelho ◽  
Rebecca Rodrigues ◽  
Jessica Guerette ◽  
Steven Wong ◽  
Dominik K. Fritz ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Activation ◽  
Adenovirus Vector ◽  
Oncostatin M ◽  
Mouse Lung ◽  
Independent Manner ◽  
Ecm Remodeling ◽  
Transient Overexpression

The accumulation of extracellular matrix in lung diseases involves numerous factors, including cytokines and chemokines that participate in cell activation in lung tissues and the circulation of fibrocytes that contribute to local fibrotic responses. The transient overexpression of the gp130 cytokine Oncostatin M can induce extracellular matrix (ECM) accumulation in mouse lungs, and here, we assess a role for IL-13 in this activity using gene deficient mice. The endotracheal administration of an adenovirus vector encoding Oncostatin M (AdOSM) caused increases in parenchymal lung collagen accumulation, neutrophil numbers, and CXCL1/KC chemokine elevation in bronchioalveolar lavage fluids. These effects were similar in IL-13-/- mice at day 7; however, the ECM matrix induced by Oncostatin M (OSM) was reduced at day 14 in the IL-13-/- mice. CD45+col1+ fibrocyte numbers were elevated at day 7 due to AdOSM whereas macrophages were not. Day 14 levels of CD45+col1+ fibrocytes were maintained in the wildtype mice treated with AdOSM but were reduced in IL-13-/- mice. The expression of the fibrocyte chemotactic factor CXCL12/SDF-1 was suppressed marginally by AdOSM in vivo and significantly in vitro in mouse lung fibroblast cell cultures. Thus, Oncostatin M can stimulate inflammation in an IL-13-independent manner in BALB/c lungs; however, the ECM remodeling and fibrocyte accumulation is reduced in IL-13 deficiency.

scholarly journals RCAN1.4 attenuates renal fibrosis through inhibiting calcineurin-mediated nuclear translocation of NFAT2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jianjian Zhang ◽  
Hui Chen ◽  
Xiaodong Weng ◽  
Hao Liu ◽  
Zhiyuan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Protein Accumulation ◽  
Adeno Associated Virus ◽  
Over Expression ◽  
Related Proteins

AbstractChronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Here, unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis in vivo, was performed on mice for a week. To overexpress RCAN1.4 in vivo, recombinant adeno-associated virus 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. The results indicated that RCAN1.4 expression was impaired both in UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. However, knocking in of RCAN1.4 suppressed the production of extracellular matrix (ECM) both in vivo and in vitro. Furthermore, in vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. In addition, we found that RCAN1.4 could rugulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. So overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting Calcineurin/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis.

scholarly journals Reverse right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension

2012 ◽  
Vol 113 (1) ◽  
pp. 149-158 ◽  
Author(s):  
Rangarajan D. Nadadur ◽  
Soban Umar ◽  
Gabriel Wong ◽  
Mansour Eghbali ◽  
Andrea Iorga ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Hypertension ◽  
Estrogen Receptor ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Estrogen Receptor Β ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Akt Phosphorylation

Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg−1·day−1, 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4′,4″-(4-propyl-[1 H]-pyrazole-1,3,5-triyl) trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β.

Tissue Fabrication: Reconstitution and Remodeling in Vitro

1991 ◽  
Vol 252 ◽  
Author(s):  
Eugene Bell ◽  
Sumi Scott
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Collagen Matrix ◽  
Dermal Fibroblasts ◽  
Matrix Remodeling ◽  
Dermal Tissue ◽  
Extracellular Matrix Components ◽  
Host Tissues

ABSTRACTTwo approaches to the reconstitution of tissues and organs are reviewed. The first consists of imitating the architecture of actual tissues and organs by combining cultured specialized cells with extracellular matrix components to produce a connective tissue substrate on or in which epithelial, mesothelial or endothelial cells can be plated or seeded and subsequently differentiate into mono or multilayered tissues and other structures. The second consists of providing an acellular framework of extracellular matrix constituents that can be occupied by adjacent host tissues after implantation in vivo and be remodeled by them to resemble the host tissues it is designed to replace. A paradigm for events in vivo, designed to study the process of remodeling of acellular matrices in vitro has been developed. The living skin equivalent (LSE), an example of a product fabricated using the first approach to tissue engineering, has been adapted to study events of extracellular matrix remodeling, relevent to the second approach to tissue engineering. After creating a disc shaped wound bed in an LSE, the wound is filled with a collagen matrix with or without added supplements and the process of epidermal wound closure and associated events in the dermis are followed. It is shown that fibroblast conditioned medium or a simple molecule such as ascorbic acid, added with no additional growth factors to the collagen matrix used to fill the wound bed, strongly stimulates the process of repair. Dermal fibroblasts from the adjacent tissue invade the collagen lattice that forms in the wound bed, and keratinocytes recruited from the wound edge overgrow the new dermal tissue. The applicability of the paradigm to the repair of vascular and other tissues will be discussed and approaches to optimizing the composition of acellular constructs considered.

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