Extracellular Matrix

ECM is a three-dimensional network made of extracellular multidomain polypeptides that provide structural and biochemical support to surrounding cells in a tissue-specific manner.

From: Advances in Protein Chemistry and Structural Biology, 2023

Extracellular Matrix

Maurice Godfrey, in Asthma and COPD (Second Edition), 2009

Introduction

Until recently the extracellular matrix was thought of solely as a static structural support network. We now know that the extracellular matrix is comprised by a large and varied group of dynamic macromolecules and their regulatory factors [1] which provides structural support and is a physical barrier. However, it also elicits cellular responses and its interactions are involved in development and organ formation [2]. Disruption of normal extracellular matrix during disease processes can lead to an inflammatory response that exacerbate aberrant remodeling of the lung [3, 4]. Much has also been learned about the role of the extracellular matrix in asthma and chronic obstructive pulmonary disease (COPD) using mouse models [5, 6]. These studies tend to support observations of altered function in people with polymorphic variants of extracellular matrix molecules [7–9].

Extracellular matrix molecules are a part of a finely regulated system of development, maintenance, and repair. In addition to the structural macromolecules that are discussed in this chapter, there are regulatory molecules that are essential components of the extracellular matrix [10, 11]. In this chapter we will review the extracellular matrix constituents of the respiratory system.

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Extracellular Matrix

Adrian Shuttleworth, in Encyclopedia of Immunology (Second Edition), 1998

Glycoproteins

The collagen family of proteins contain a triple helical portion in their structure, and the proteoglycans all contain GAG chains attached to a protein core. Matrix glycoproteins, however, apart from containing O-linked and/or N-linked sugars, appear to have little in common with one another. Functionally, the ability to interact with other matrix molecules and with cells appears to be the common feature of this class of molecule, and a number have been described as ‘adhesive glycoproteins’.

Many of the matrix glycoproteins contain distinct and functionally active protein domains that prescribe interactions with the cell surface as well as other matrix molecules. In addition, a number of the molecules form oligomers, and families of molecules are produced by alternative splicing. Many possess short aspartate-containing sequences such as RGD, which mediate cellular adhesion through the integrin family of membrane receptors.

Fibronectin is found in the ECM and blood plasma; it contains two nonidentical subunits joined by disulfide bonds and is the best characterized of the adhesive glycoproteins. The domain structure of one of the subunits is shown in Figure 3, and different domains are specialized for binding extracellular matrix molecules of bacterial or eukaryotic membrane receptors. Different fibronectin isoforms arise by alternative splicing of the transcript of a single gene. Its principal functions appear to be in cellular migration during development and wound healing, regulation of cell growth and differentiation, and hemostasis and thrombosis.

Figure 3. Domain structure of one of the subunits of fibronectin. FN type I repeats (□), FN type II repeats (■) and the FN type III repeats (▨) are shown. The three type III repeats that undergo alternative splicing are indicated. The number of additional amino acids (aa) encoded by splice variants of the third FN type III segment are indicated.

Many mesenchymal cells preferentially use fibronectin to adhere to; in contrast epithelial and endothelial cells use the glycoprotein laminin. Laminins are present in all basement membranes and have major influences on adhesion, growth, migration and differentiation of cells. Laminins are composed of three chains (α, β and γ) with molecular weights of 140–400 kDa. At present eight genetically distinct laminin chains and seven different assemblies are known. Chain association occurs through an α-helical coiled coil near the C-terminus of each chain. The specific binding of laminins to perlecan, entactin, type IV collagen and other basement membrane components suggests that laminins play a crucial role in the supramolecular organization and assembly of basement membranes.

The type III repeat of fibronectin containing the RGDS cell-binding motif is found in a number of matrix glycoproteins, including thrombospondin and tenascin, and is probably a recurring motif for cell binding. Another common domain in matrix glycoproteins is the epidermal growth factor (EGF) repeat. In addition to laminin, entactin, thrombospondin and tenascin, it is found in the proteoglycans aggrecan and versican. These repeats may mediate two functions: first, facilitate protein–protein interactions; and second, interact with EGF receptors and control cellular activity. The occurrence of multiple domains in the glycoproteins suggests multiple functions, and during evolution this has been achieved by exon shuffling, which has produced the variety of matrix glycoproteins.

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Brain Extracellular Matrix in Health and Disease

Andre Zeug, ... Evgeni Ponimaskin, in Progress in Brain Research, 2014

Abstract

The extracellular matrix (ECM) occupies the space between both neurons and glial cells and thus provides a microenvironment that regulates multiple aspects of neural activities. Because of the vital role of ECM as a natural environment of cells in vivo, there is a growing interest to develop methodology allowing for the detailed structural and functional analyses of ECM. In this chapter, we provide the detailed overview of current microscopic methods used for ECM analysis and also describe general labeling strategies for ECM visualization. Since ECM remodeling involves the proteolytic cleavage of ECM, we will also describe current experimental approaches to image the proteolytic reorganization and/or degradation of ECM. The special focus of this chapter is set to the application of Förster resonance energy transfer-based approaches to monitor intracellular and extracellular matrix functions with high spatiotemporal resolution.

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Extracellular Matrix as an Inductive Scaffold for Functional Tissue Reconstruction

Bryan N. Brown, Stephen F. Badylak, in Translating Regenerative Medicine to the Clinic, 2016

Abstract

The extracellular matrix (ECM) is a complex network of both structural and functional proteins assembled in unique tissue-specific architectures. The ECM provides both a mechanical framework for each tissue and organ and an inductive substrate for cell signaling. The ECM is highly dynamic and cells receive signals from the ECM and contribute to its content and organization. This process of “dynamic reciprocity” is key to tissue development and for homeostasis. Based upon these important functions, ECM-based materials have been used in a wide variety of tissue engineering and regenerative medicine approaches to functional tissue reconstruction. It has been shown that ECM-based materials, when appropriately prepared, can act as facilitators of stem cell migration and macrophage phenotype modulation that promote de novo functional, site-appropriate, tissue formation. Herein, the diverse structural and functional roles of the ECM are reviewed to provide a rationale for the use of ECM scaffolds in regenerative medicine. Translational examples of ECM scaffolds are given and the potential mechanisms by which ECM scaffolds elicit constructive remodeling are discussed.

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Comparative Biology of the Normal Lung Extracellular Matrix

Stephanie A. Matthes, ... Eric S. White, in Comparative Biology of the Normal Lung (Second Edition), 2015

Abstract

The extracellular matrix (ECM) of the lung provides tensile strength, intrinsic elasticity, and a substrate upon which cells reside and function. The ECM is comprised of a multitude of glycoproteins, proteoglycans, and other molecules whose ultimate composition and arrangements allow for the normal functioning of the various lung compartments. Despite decades of investigation, we are only now beginning to better understand the composition of the human lung ECM. Recent technological advances now allow a direct comparison of human lung ECM with that of experimental animal models, confirming or refuting previous observations. This chapter outlines the known components of the ECM, explores our current knowledge of lung ECM from embryonic development through postnatal life, and discusses newer techniques available to isolate and better study lung ECM.

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Extracellular Matrix Molecules: Synaptic Plasticity and Learning

A. Dityatev, ... M. Schachner, in Encyclopedia of Neuroscience, 2009

Conclusions and Future Directions

Several ECM molecules have been identified as crucial players in hippocampal synaptic plasticity and learning and memory (Table 1). The signaling events underlying the contributions of these and probably other ECM molecules to synaptic functions remain to be elucidated, particularly at the presynaptic level. Yet we believe that it can be concluded that the ECM in the nervous system is much more than just a passive microenvironment repellant or conducive for cells and neurites. Tight functional links to synaptic plasticity and learning, together with data showing remarkable activity and learning-induced changes in expression of ECM molecules and enzymes involved in remodeling of the ECM in the adult nervous system, suggest that the ECM is a dynamic, functionally indispensable structure between glial cells and their pre- and postsynaptic neuronal partners.

Table 1. ECM molecules, synaptic plasticity, and learning and memory

FunctionsECM molecules
Synaptic plasticity
Activity of NMDARsReelin, integrin ligand(s)
Activity of L-type Ca2+ channelsTenascin-C
GABAergic inhibitionTenascin-R, HB-GAM
Activity/recycling of AMPARsIntegrin ligand(s)
Activity of Rho/ROCKRPTPβ
Unknown mechanismsBrevican, neurocan
Learning and memory
Water mazeTenascin-R, HNK-1, integrin ligand(s), RPTPβ, brevicana
Contextual fear conditioningReelin, tenascin-C (on extinction)
One-trial passive avoidanceBiglycan, heparin
Working memoryIntegrin ligand(s)
a
Only tendencies were observed in a small number of mice.
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Cell-derived Matrices - Part A

Insung Yong, ... Pilnam Kim, in Methods in Cell Biology, 2020

Abstract

An extracellular matrix (ECM) has both biochemical and mechanophysical characteristics obtained from multiple components, which provides cells a dynamic microenvironment. During reciprocal interactions with ECM, the cells actively remodel the matrix, including synthesis, degradation, and chemical modification, which play a pivotal role in various biological events such as disease progression or tissue developmental processes. Since a cell-derived decellularized ECM (cdECM) holds in vivo-like compositional heterogeneity and interconnected fibrillary architecture, it has received much attention as a promising tool for developing more physiological in vitro model systems. Despite these advantages, the cdECM has obvious limitations to mimic versatile ECMs precisely, suggesting the need for improved in vitro modeling to clarify the functions of native ECM. Recent studies propose to tailor the cdECM via biochemically, biomechanically, or incorporation with other systems as a new approach to address the limitations. In this chapter, we summarize the studies that re-engineered the cdECM to examine the features of native ECM in-depth and to increase physiological relevancy.

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Brain Extracellular Matrix in Health and Disease

Bart R. Lubbers, ... Michel C. van den Oever, in Progress in Brain Research, 2014

Abstract

The extracellular matrix (ECM) has a prominent role in brain development, maturation of neural circuits, and adult neuroplasticity. This multifactorial role of the ECM suggests that processes that affect composition or turnover of ECM in the brain could lead to altered brain function, possibly underlying conditions of impaired mental health, such as neuropsychiatric or neurodegenerative disease. In support of this, in the last two decades, clinical and preclinical research provided evidence of correlations and to some degree causal links, between aberrant ECM function and neuropsychiatric disorders, the most prominent being addiction and schizophrenia. Based on these initial observations of involvement of different classes of ECM molecules (laminin, reelin, and their integrin receptors, as well as tenascins and chondroitin sulfate proteoglycans), ECM targets have been suggested as a novel entry point in the treatment of neuropsychiatric disorders. Hence, understanding how ECM molecules contribute to proper neuronal functioning and how this is dysregulated in conditions of mental illness is of pivotal importance. In this chapter, we will review available literature that implicates the different classes of brain ECM molecules in psychiatric disorders, with a primary focus on addiction (opiates, psychostimulants, and alcohol), and we will compare these ECM adaptations with those implicated in schizophrenia and mood disorders.

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Matrix Effects

Jeffrey A. Hubbell, in Principles of Tissue Engineering (Fourth Edition), 2014

Abstract

The extracellular matrix is a complex chemically and physically crosslinked network of proteins and glycosaminoglycans. This matrix serves to organize cells in space, to provide them with environmental signals to direct site-specific cellular regulation and to separate one tissue space from another. The interaction between cells and the extracellular matrix is bi-directional and dynamic: cells are constantly accepting information about their environment from cues in the extracellular matrix, and cells are frequently remodeling their extracellular matrix. In this chapter, the proteins in the extracellular matrix and their cell-surface receptors are introduced, and mechanisms by which cells transduce chemical information in their extracellular matrix are discussed. The complex interplay between signaling from matrix molecules and associated growth factors is presented. Methods for spatially displaying matrix recognition factors on and in biomaterials is described, both in the context of model systems for investigation of cellular behavior and from the perspective of creation of bioactive biomaterials for tissue-engineering therapies.

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Carcinogenesis

C.J. Conti, in Comprehensive Toxicology, 2010

14.16.3.4.2 Changes in the extracellular matrix

The ECM plays a central role in tissue homeostasis. It has an obvious structural function serving as the scaffold of tissue organization and forming biological barriers between tissues with different functions (Nelson and Bissell 2006). In addition, the ECM plays a regulatory function, by means of numerous binding proteins that interact with integrins and other cell surface proteins affecting cell growth and differentiation. Furthermore, the ECM is the most important reservoir of growth factors that can be rapidly released upon a variety of stimuli (DeClerck et al. 2004). A large body of literature supports the concept that the ECM of normal adult tissues is different from the ECM of tumors but the latter has many similarities with the ECMs found in embryonary tissues as well as in adult tissues in the process of regeneration. The ECM of regenerative tissues and tumors is rich in collagen 1, fibronectin, proteoglycans, and glycosaminoglycans (Nelson and Bissell 2006). More importantly, it has elevated proteolytic activity in virtue of enzymes secreted by CAFs, macrophages, and neoplastic cells. This elevated proteolytic activity generates biologically active fragments derived from the ECM proteins and activate growth factors associated with the ECM. Proteolytic activity is also responsible for the changes in the nature of epitopes involved in cell interaction with the ECM and cell–cell interactions (Littlepage et al. 2008; Nelson and Bissell 2006).

Physicochemical alterations of the ECM are also present in tumors. The contractile activity of CAFs and leakiness of tumoral blood vessels produce changes in tissue tensions (increased hydrostatic pressure in the ECM) that affect tissue morphogenesis and facilitate metastasis (Nelson and Bissell 2006). The inflammatory process in the ECM is also one of the major sources of reactive oxygen species (ROS) that affect tumor progression as a result of its mutagenic properties (Tlsty and Coussens 2006).

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