Neocortical expansion, thought to underlie the cognitive traits unique to humans, is accompanied by cortical folding. This folding starts around gestational week (GW) 20, but what causes it remains ...largely unknown. Extracellular matrix (ECM) has been previously implicated in neocortical expansion and here we investigate the potential role of ECM in the formation of neocortical folds. We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1 (HAPLN1), lumican and collagen I (collectively, HLC). Addition of HLC to cultures of human fetal neocortex (11–22 GW) caused local changes in tissue stiffness, induced CP folding, increased CP hyaluronic acid (HA), and required the HA-receptor CD168 and downstream ERK signaling. Importantly, loss of HA reduced HLC-induced and 22 GW physiological nascent folds. This was altered in samples with neurodevelopmental disorders, indicating it may be a useful system to study such disorders.
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•ECM components HAPLN1, lumican and collagen I (HLC) induce human neocortex folding•HLC-induced folding involves increases in ECM stiffness and requires HA/CD168/ERK•Degradation of HA reduces physiological folds in 22 GW human neocortex•HLC-induced cortical folding is impaired in certain neurodevelopmental disorders
Folding of the human neocortex is a key feature of its evolutionary expansion. Here, Long et al. identify a novel extracellular matrix-driven mechanism underlying human neocortex folding, and disruption of this mechanism perturbs the physiological folding of human neocortical tissue.
In response to myocardial infarction (MI), cardiac macrophages regulate inflammation and scar formation. We hypothesized that macrophages undergo polarization state changes over the MI time course ...and assessed macrophage polarization transcriptomic signatures over the first week of MI. C57BL/6 J male mice (3–6 months old) were subjected to permanent coronary artery ligation to induce MI, and macrophages were isolated from the infarct region at days 1, 3, and 7 post-MI. Day 0, no MI resident cardiac macrophages served as the negative MI control. Whole transcriptome analysis was performed using RNA-sequencing on
n
= 4 pooled sets for each time. Day 1 macrophages displayed a unique pro-inflammatory, extracellular matrix (ECM)-degrading signature. By flow cytometry, day 0 macrophages were largely F4/80
high
Ly6C
low
resident macrophages, whereas day 1 macrophages were largely F4/80
low
Ly6C
high
infiltrating monocytes. Day 3 macrophages exhibited increased proliferation and phagocytosis, and expression of genes related to mitochondrial function and oxidative phosphorylation, indicative of metabolic reprogramming. Day 7 macrophages displayed a pro-reparative signature enriched for genes involved in ECM remodeling and scar formation. By triple in situ hybridization, day 7 infarct macrophages in vivo expressed collagen I and periostin mRNA. Our results indicate macrophages show distinct gene expression profiles over the first week of MI, with metabolic reprogramming important for polarization. In addition to serving as indirect mediators of ECM remodeling, macrophages are a direct source of ECM components. Our study is the first to report the detailed changes in the macrophage transcriptome over the first week of MI.
Abstract
Myocardial fibrosis, the expansion of the cardiac interstitium through deposition of extracellular matrix proteins, is a common pathophysiologic companion of many different myocardial ...conditions. Fibrosis may reflect activation of reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. Immune cells, vascular cells and cardiomyocytes may also acquire a fibrogenic phenotype under conditions of stress, activating fibroblast populations. Fibrogenic growth factors (such as transforming growth factor-β and platelet-derived growth factors), cytokines including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, and IL-4, and neurohumoral pathways trigger fibrogenic signalling cascades through binding to surface receptors, and activation of downstream signalling cascades. In addition, matricellular macromolecules are deposited in the remodelling myocardium and regulate matrix assembly, while modulating signal transduction cascades and protease or growth factor activity. Cardiac fibroblasts can also sense mechanical stress through mechanosensitive receptors, ion channels and integrins, activating intracellular fibrogenic cascades that contribute to fibrosis in response to pressure overload. Although subpopulations of fibroblast-like cells may exert important protective actions in both reparative and interstitial/perivascular fibrosis, ultimately fibrotic changes perturb systolic and diastolic function, and may play an important role in the pathogenesis of arrhythmias. This review article discusses the molecular mechanisms involved in the pathogenesis of cardiac fibrosis in various myocardial diseases, including myocardial infarction, heart failure with reduced or preserved ejection fraction, genetic cardiomyopathies, and diabetic heart disease. Development of fibrosis-targeting therapies for patients with myocardial diseases will require not only understanding of the functional pluralism of cardiac fibroblasts and dissection of the molecular basis for fibrotic remodelling, but also appreciation of the pathophysiologic heterogeneity of fibrosis-associated myocardial disease.
Extracellular matrix (ECM) is an extraordinarily complex and unique meshwork composed of structural proteins and glycosaminoglycans. The ECM provides essential physical scaffolding for the cellular ...constituents, as well as contributes to crucial biochemical signaling. Importantly, ECM is an indispensable part of all biological barriers and substantially modulates the interchange of the nanotechnology products through these barriers. The interactions of the ECM with nanoparticles (NPs) depend on the morphological characteristics of intercellular matrix and on the physical characteristics of the NPs and may be either deleterious or beneficial. Importantly, an altered expression of ECM molecules ultimately affects all biological processes including inflammation. This review critically discusses the specific behavior of NPs that are within the ECM domain, and passing through the biological barriers. Furthermore, regenerative and toxicological aspects of nanomaterials are debated in terms of the immune cells-NPs interactions.
Extracellular matrix (ECM) is a non-cellular three-dimensional macromolecular network composed of collagens, proteoglycans/glycosaminoglycans, elastin, fibronectin, laminins, and several other ...glycoproteins. Matrix components bind each other as well as cell adhesion receptors forming a complex network into which cells reside in all tissues and organs. Cell surface receptors transduce signals into cells from ECM, which regulate diverse cellular functions, such as survival, growth, migration, and differentiation, and are vital for maintaining normal homeostasis. ECM is a highly dynamic structural network that continuously undergoes remodeling mediated by several matrix-degrading enzymes during normal and pathological conditions. Deregulation of ECM composition and structure is associated with the development and progression of several pathologic conditions. This article emphasizes in the complex ECM structure as to provide a better understanding of its dynamic structural and functional multipotency. Where relevant, the implication of the various families of ECM macromolecules in health and disease is also presented.
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The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key ...signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.
Zebrafish can regenerate their hearts. The role of the extracellular matrix in this process is largely unknown. We have analyzed the proteome in control hearts and at different times of regeneration. ...Decellularization of samples allowed for enrichment of extracellular matrix proteins, increasing their detection. The results reported dynamic changes in specific proteins associated with specific stages of the regenerative process. Biomechanical analysis by atomic force microscopy revealed concomitant changes in matrix stiffness during this process.
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Highlights
•We have developed a decellularization protocol for ECM protein enrichment.•We have characterized the proteome of adult zebrafish heart ECM.•We describe dynamic changes in heart ECM proteome during regeneration.•We describe changes in heart ECM stiffness during regeneration.
Adult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days postamputation) time point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.
The evolution of extracellular matrix Ozbek, Suat; Balasubramanian, Prakash G; Chiquet-Ehrismann, Ruth ...
Molecular biology of the cell,
12/2010, Letnik:
21, Številka:
24
Journal Article
Recenzirano
Odprti dostop
We present a perspective on the molecular evolution of the extracellular matrix (ECM) in metazoa that draws on research publications and data from sequenced genomes and expressed sequence tag ...libraries. ECM components do not function in isolation, and the biological ECM system or "adhesome" also depends on posttranslational processing enzymes, cell surface receptors, and extracellular proteases. We focus principally on the adhesome of internal tissues and discuss its origins at the dawn of the metazoa and the expansion of complexity that occurred in the chordate lineage. The analyses demonstrate very high conservation of a core adhesome that apparently evolved in a major wave of innovation in conjunction with the origin of metazoa. Integrin, CD36, and certain domains predate the metazoa, and some ECM-related proteins are identified in choanoflagellates as predicted sequences. Modern deuterostomes and vertebrates have many novelties and elaborations of ECM as a result of domain shuffling, domain innovations and gene family expansions. Knowledge of the evolution of metazoan ECM is important for understanding how it is built as a system, its roles in normal tissues and disease processes, and has relevance for tissue engineering, the development of artificial organs, and the goals of synthetic biology.
Abstract
Thyroid-associated orbitopathy (TAO) is a disfiguring periocular connective tissue disease associated with autoimmune thyroid disorders. It is a potentially blinding condition, for which no ...effective pharmacological treatment has been established. Despite a suggested role played by autoimmune thyrotropin receptor activation in the pathogenesis of TAO, the cellular and molecular events contributing to the fibrotic and inflammatory disease process of TAO are not fully defined. By developing a three-dimensional organoid culture of human orbital fibroblasts (OFs), we sought to determine the molecular mechanism underlying the fibrotic disease process of TAO. In this ex vivo model, we have demonstrated that hypoxia-inducible factor (HIF) 2α (HIF2A), but not its paralog HIF1A, accelerates extracellular matrix (ECM) deposition by inducing a collagen–cross-linking enzyme, lysyl oxidase (LOX). Inhibiting HIF2A and LOX with short hairpin RNA or small molecular antagonists effectively ameliorated fibrotic disease process within TAO organoids. Conversely, the overexpression of a constitutively active HIF2A in mouse OFs was sufficient to initiate LOX-dependent fibrotic tissue remodeling in OF organoids. Consistent with these findings, HIF2A and LOX were highly expressed in human TAO tissues paralleling excess ECM deposition. We propose that the HIF2A–LOX pathway can be a potential therapeutic target for the prevention and treatment of TAO.
Syndecans are a small family of four transmembrane proteoglycans in mammals. They have similar structural organization, consisting of an N‐terminal ectodomain, single transmembrane domain and ...C‐terminal cytoplasmic domain. Over the years, the association between syndecans and the actin cytoskeleton has been established, which has consequences for the regulation of cell adhesion and migration. Specifically, ecto‐ and cytoplasmic domains are responsible for the interaction with extracellular matrix molecules and intracellular kinases, respectively. These interactions indicate syndecans as key molecules during cancer initiation and progression. Particularly syndecans interact with other cell surface receptors, such as growth factor receptors and integrins, which lead to activation of downstream signaling pathways, which are critical for the cellular behavior. Moreover, this review describes the key role of syndecans in intracellular calcium regulation and homeostasis. The syndecan‐mediated regulation of calcium metabolism is highly correlated with cells’ adhesion phenotype through the actin cytoskeleton and formation of junctions, with implications during differentiation and disease progression.
The interplay of syndecans with growth factor receptors, integrins and ion channels contributes to the regulation of cell functional properties, morphology and signaling. Syndecans, and especially syndecan‐4, associated with actin cytoskeleton regulate cell migration and adhesion during developmental procedures and tumorigenesis. Pharmacological targeting of syndecans biological actions will be a useful tool for the treatment of several diseases and especially cancer.
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