scholarly journals Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

2018 ◽  
Author(s):  
Hyun-Taek Kim ◽  
Wenguang Yin ◽  
Young-June Jin ◽  
Paolo Panza ◽  
Felix Gunawan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Alveolar Epithelium ◽  
Mouse Lung ◽  
Chain Gene ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Muscle Myosin ◽  
Alveolar Formation ◽  
Deposition Defects

AbstractImpaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

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 Bone Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling of Degenerated Nucleus Pulposus Cells via the miR-101-3p/EIF4G2 Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zeng Wang ◽  
Xiaolin Ding ◽  
Feifei Cao ◽  
Xishan Zhang ◽  
Jingguo Wu
Keyword(s):  
Extracellular Matrix ◽  
Nucleus Pulposus ◽  
Quantitative Polymerase Chain Reaction ◽  
Matrix Remodeling ◽  
Nucleus Pulposus Cells ◽  
Promoting Effect ◽  
Bone Mesenchymal Stem Cells ◽  
Ecm Remodeling ◽  
Lumbar Vertebral Fracture ◽  
Related Proteins

The etiology of lumbocrural pain is tightly concerned with intervertebral disk degeneration (IDD). Bone mesenchymal stem cell (BMSC)-based therapy bears potentials for IDD treatment. The properties of microRNA (miRNA)-modified BMSCs may be altered. This study investigated the role and mechanism of BMSCs promoting extracellular matrix (ECM) remodeling of degenerated nucleus pulposus cells (NPCs) via the miR-101-3p/EIF4G2 axis. NPCs were collected from patients with IDD and lumbar vertebral fracture (LVF). The expressions of miR-101-3p and ECM-related proteins, Collagen-I (Col-I) and Collagen-II (Col-II), were detected using the reverse transcription-quantitative polymerase chain reaction. The expressions of Col-I and Col-II, major non-collagenous component Aggrecan, and major catabolic factor Matrix metalloproteinase-13 (MMP-13) were detected using Western blotting. BMSCs were cocultured with degenerated NPCs from patients with IDD. Viability and apoptosis of NPCs were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. After the degenerated NPCs were transfected with the miR-101-3p inhibitor, the expressions of ECM-related proteins, cell viability, and apoptosis were detected. The targeting relationship between miR-101-3p and EIF4G2 was verified. Functional rescue experiments verified the effects of miR-101-3p and EIF4G2 on ECM remodeling of NPCs. Compared with the NPCs of patients with LVF, the degenerated NPCs of patients with IDD showed downregulated miR-101-3p, Col-II, and Aggrecan expressions and upregulated MMP-13 and Col-I expressions. BMSCs increased the expressions of miR-101-3p, Aggrecan, and Col-II, and decreased the expressions of MMP-13 and Col-I in degenerated NPCs. BMSCs enhanced NPC viability and repressed apoptosis. Downregulation of miR-101-3p suppressed the promoting effect of BMSCs on ECM remodeling. miR-101-3p targeted EIF4G2. Downregulation of EIF4G2 reversed the inhibiting effect of the miR-101-3p inhibitor on ECM remodeling. In conclusion, BMSCs increased the miR-101-3p expression in degenerated NPCs to target EIF4G2, thus promoting the ECM remodeling of NPCs.

scholarly journals Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Cheri L. Lamb ◽  
Giovan N. Cholico ◽  
Daniel E. Perkins ◽  
Michael T. Fewkes ◽  
Julia Thom Oxford ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Matrix Remodeling ◽  
Mrna Levels ◽  
Gelatinase Activity ◽  
Ecm Remodeling ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.

scholarly journals Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R

2020 ◽  
Author(s):  
Tal M. Dankovich ◽  
Rahul Kaushik ◽  
Gabriel Cassinelli Petersen ◽  
Philipp Emanuel Giro ◽  
Hannah Abdul Hadi ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Protein Synthesis ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Activity Dependent ◽  
The Brain ◽  
Brain Extracellular Matrix

SummaryThe brain extracellular matrix (ECM) assembles around neurons and synapses, and is thought to change only rarely, through proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. We found that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within ∼3 days, in an activity-dependent fashion.

Abstract 122: Pharmacological Inhibition Of Macrophage Infiltration Prevents Myxomatous Valve Degeneration In Marfan Syndrome

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Na Xu ◽  
Katherine E Yutzey
Keyword(s):  
Immune Response ◽  
Extracellular Matrix ◽  
Marfan Syndrome ◽  
Macrophage Infiltration ◽  
Histological Evaluation ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Mitral Valves ◽  
Fibrillin 1 ◽  
Underlying Mechanisms

Introduction: Myxomatous valve degeneration (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. Currently, there is no medical therapy for the treatment of MVD. MVD in a mouse model of Marfan syndrome (MFS) is characterized leaflet thickening and increased macrophage infiltration, which are reduced with loss of C-C chemokine receptor type 2 (CCR2). However, the specific contributions of macrophages to pathological extracellular matrix (ECM) remodeling and underlying mechanisms are unknown. Hypothesis: Inhibition of macrophage infiltration by a CCR2 inhibitor blocks ECM abnormalities and MVD progression in mitral valves of MFS mice by suppressing the response to cytokine/chemokines. Methods: Mice with the mutation of Fibrillin 1 (Fbn1 C1039G/+ ) recapitulate histopathological features of MFS. Here, we tested the efficacy of a selective CCR2 antagonist RS504393 in the valves of MFS mice in the initiation (1-month-old) and the progression (2-month-old) of MVD, respectively. MFS mice were intraperitoneally injected with RS504393 at 2 mg/kg/d for 30 days. Histological evaluation and immunofluorescence for macrophages and ECM were performed. RNAseq was performed in mitral valves from 2-month old Fbn1 C1039G/+ mice with CCR2 knockout (CCR2 RFP/RFP ). Results: MFS valves revealed ECM abnormalities characterized by collagen fragmentation and proteoglycan accumulation. RS504393 treatment reduced infiltrating macrophages (MHCII+, CCR2+) in myxomatous valves. Remarkably, RS504393 was protective against both the initiation and the progression of MVD, detected by decreased mitral valve thickness and prevention of pathological ECM remodeling in MFS mice. RNAseq data confirmed increased leukocyte activation involved in immune response and abnormal extracellular matrix remodeling in MFS valves. CCR2 deficiency blocked macrophage infiltration and inhibited the response to cytokines in Fbn1 C1039G/+ valves. Conclusions: Our results show that macrophage infiltration is critical for progressive MVD. Moreover, CCR2 inhibition ameliorates MVD progression by preventing immune response. Thus, the CCR2 inhibitor RS504393 is a potential pharmacological candidate to treat MVD in MFS.

scholarly journals Sex-based difference in Achilles peritendinous levels of matrix metalloproteinases and growth factors after acute resistance exercise

2017 ◽  
Vol 122 (2) ◽  
pp. 361-367 ◽  
Author(s):  
Broc D. Astill ◽  
Mark S. Katsma ◽  
David J. Cauthon ◽  
Jason Greenlee ◽  
Mark Murphy ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Resistance Exercise ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Matrix Remodeling ◽  
Similar Extent ◽  
Acute Bout ◽  
Men And Women ◽  
Ecm Remodeling ◽  
Structural And Functional Properties

Several recent investigations have demonstrated that the ability of various tendons to alter structural and functional properties in response to exercise are muted in women compared with men. We hypothesize that this disparity between men and women may be due to a reduced tendon production of key mediators of tendon extracellular matrix (ECM) remodeling in response to mechanical loading, e.g., exercise. Using microdialysis before and after an acute bout of resistance exercise, we evaluated Achilles peritendinous levels of insulin-like growth factor-1 (IGF-1) and interleukin-6 (IL-6), which have both been shown to increase tendon collagen synthesis. Additionally, the matrix remodeling enzymes matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also evaluated. IGF-1 levels were elevated ( P < 0.05) to a similar extent in men and women after 3 h of exercise but remained elevated at 4 h in only women. IL-6 levels were ~4-fold greater after exercise in both men and women ( P < 0.05). MMP-2 levels increased to a similar extent (~2-3-fold) in men and women ( P < 0.05). In contrast, MMP-9 increased with exercise but only in men ( P < 0.05). Last, TIMP-1 levels also increased ( P < 0.05) with exercise in men and women but the increase was more prolonged in women. In conclusion, we observed modest sex differences in tendon release of MMP-9, TIMP-1, and IGF-1 after acute resistance exercise. If such differences persist throughout a chronic exercise training, they may contribute to the reduced ability of women to adapt to exercise compared with men. NEW & NOTEWORTHY In this investigation we utilized microdialysis of the peritendinous Achilles to evaluate potential differences between men and women in tendon production of key regulators of extracellular matrix remodeling. We demonstrate that a modest sex-specific difference exists in peritendinous levels of several key extracellular matrix modulators after an acute bout of resistance exercise.

scholarly journals Extracellular matrix remodeling in animal models of anthracycline-induced cardiomyopathy: a meta-analysis

2021 ◽  
Author(s):  
Jan M. Leerink ◽  
Mabel van de Ruit ◽  
Elizabeth A.M. Feijen ◽  
Leontien C.M. Kremer ◽  
Annelies M.C. Mavinkurve-Groothuis ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Natriuretic Peptide ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Differentially Expressed ◽  
Ecm Remodeling ◽  
Protein Levels

AbstractAs in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1–8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function.

scholarly journals Tumor Extracellular Matrix Remodeling: New Perspectives as a Circulating Tool in the Diagnosis and Prognosis of Solid Tumors

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 81 ◽  
Author(s):  
Marta Giussani ◽  
Tiziana Triulzi ◽  
Gabriella Sozzi ◽  
Elda Tagliabue
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Tumor Tissue ◽  
Prognostic Markers ◽  
Complex Mixture ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Diagnosis And Prognosis ◽  
Novel Concept

: In recent years, it has become increasingly evident that cancer cells and the local microenvironment are crucial in the development and progression of tumors. One of the major components of the tumor microenvironment is the extracellular matrix (ECM), which comprises a complex mixture of components, including proteins, glycoproteins, proteoglycans, and polysaccharides. In addition to providing structural and biochemical support to tumor tissue, the ECM undergoes remodeling that alters the biochemical and mechanical properties of the tumor microenvironment and contributes to tumor progression and resistance to therapy. A novel concept has emerged, in which tumor-driven ECM remodeling affects the release of ECM components into peripheral blood, the levels of which are potential diagnostic or prognostic markers for tumors. This review discusses the most recent evidence on ECM remodeling-derived signals that are detectable in the bloodstream, as new early diagnostic and risk prediction tools for the most frequent solid cancers.

scholarly journals Skeletal Muscle Extracellular Matrix Remodeling with Worsening Glycemic Control in Nonhuman Primates

2020 ◽  
Author(s):  
Alistaire D. Ruggiero ◽  
Ashley Davis ◽  
Chrissy Sherrill ◽  
Brian Westwood ◽  
Gregory A. Hawkins ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Blood Glucose ◽  
Glycemic Control ◽  
Fasting Blood Glucose ◽  
Rational Approach ◽  
Specific Gene ◽  
Matrix Remodeling ◽  
Ecm Remodeling

Type 2 diabetes (T2D) development may be mediated by skeletal muscle (SkM) function, which is responsible for >80% of circulating glucose uptake. The goals of this study were to assess changes in global and location-level gene expression, remodeling proteins, fibrosis and vascularity of SkM with worsening glycemic control, through RNA sequencing, immunoblotting and immunostaining. We evaluated SkM samples from health-diverse African green monkeys (Cholorcebus aethiops sabaeus) to investigate these relationships. We assessed SkM remodeling at the molecular level by evaluating unbiased transcriptomics in age, sex, and weight and waist circumference-matched metabolically healthy, pre-diabetic (Pre-T2D) and T2D monkeys (n=13). Our analysis applied novel location-specific gene differences and shows that extracellular facing and cell membrane-associated genes and proteins are highly upregulated in metabolic disease. We verified transcript patterns using immunohistochemical staining and protein analyses of MMP16, TIMP2 and VEGF. Extracellular matrix (ECM) functions to support intercellular communications, including the coupling of capillaries to muscle cells, which was worsened with increasing blood glucose. Multiple regression modeling from age- and health-diverse monkeys (n=33) revealed that capillary density was negatively predicted only by fasting blood glucose. The loss of vascularity in SkM co-occurred with reduced expression of hypoxia-sensing genes, which is indicative of a disconnect between altered ECM and reduced endothelial cells, and known perfusion deficiencies present in IR and T2D. This report supports that rising blood glucose values incite ECM remodeling and reduce SkM capillarization, and that targeting ECM would be a rational approach to improve health with metabolic disease.

scholarly journals Levels of Circulating MMCN-151, a Degradation Product of Mimecan, Reflect Pathological Extracellular Matrix Remodeling in Apolipoprotein E Knockout Mice

2011 ◽  
Vol 6 ◽  
pp. BMI.S7777 ◽  
Author(s):  
N. Barascuk ◽  
E. Vassiliadis ◽  
Q. Zheng ◽  
Y. Wang ◽  
W. Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Apolipoprotein E ◽  
Enzyme Linked Immunosorbent Assay ◽  
Matrix Remodeling ◽  
Limit Of Quantification ◽  
Ecm Remodeling ◽  
Apolipoprotein E Knockout Mice ◽  
Significant Difference ◽  
Apoe Ko Mice ◽  
Apoe Ko

Aim Arterial extracellular matrix (ECM) remodeling by matrix metalloproteinases (MMPs) is one of the major hallmarks of atherosclerosis. Mimecan, also known as osteoglycin has been implicated in the integrity of the ECM. This study assessed the validity of an enzyme-linked immunosorbent assay (ELISA) developed to measure a specific MMP12-derived fragment of mimecan, MMCN-151, in apolipoprotein-E knockout (ApoE-KO) mice. Methods and Results A mouse monoclonal antibody raised against MMCN-151 was used to develop a competitive ELISA. The assay was validated using samples from 20 ApoE-KO and 20 wild type [C57 BL/6] male mice fed a normal or high-fat diet (HFD) for up to 20 weeks. The technical reliability of the assay was established with intra-assay variability <2% and inter-assay variability < 10%. The lowest limit of quantification of MMCN-151 was 0.5 ng/ml. ApoE-KO mice fed a HFD for 20 weeks had four-fold increased circulating levels of MMCN-151 compared to baseline, whereas MMCN-151 levels in control mice on HFD increased two-fold compared with baseline. After 10 weeks of a HFD, a significant difference in MMCN-151 levels was observed between ApoE-KO and control mice ( P = 0.005) and became more significant at 20 weeks ( P = 0.002). Conclusions The newly developed assay is a reliable detector of MMCN-151 levels which ultimately may be useful indicators of arterial remodeling in patients affected by atherosclerotic disease.

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