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Nitti, P.; Narayanan, A.; Pellegrino, R.; Villani, S.; Madaghiele, M.; Demitri, C. Extracellular Matrix (ECM). Encyclopedia. Available online: https://encyclopedia.pub/entry/49959 (accessed on 18 May 2024).
Nitti P, Narayanan A, Pellegrino R, Villani S, Madaghiele M, Demitri C. Extracellular Matrix (ECM). Encyclopedia. Available at: https://encyclopedia.pub/entry/49959. Accessed May 18, 2024.
Nitti, Paola, Athira Narayanan, Rebecca Pellegrino, Stefania Villani, Marta Madaghiele, Christian Demitri. "Extracellular Matrix (ECM)" Encyclopedia, https://encyclopedia.pub/entry/49959 (accessed May 18, 2024).
Nitti, P., Narayanan, A., Pellegrino, R., Villani, S., Madaghiele, M., & Demitri, C. (2023, October 09). Extracellular Matrix (ECM). In Encyclopedia. https://encyclopedia.pub/entry/49959
Nitti, Paola, et al. "Extracellular Matrix (ECM)." Encyclopedia. Web. 09 October, 2023.
Extracellular Matrix (ECM)
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This entry is adapted from the peer-reviewed paper 10.3390/bioengineering10101122

In tissues and organs, the extracellular matrix (ECM) is an essential extracellular element that surrounds cells, characterised by its sophisticated nanoarchitecture. It is a highly hydrated structure composed of cell-secreted proteins (e.g., collagen, fibronectin, elastin, etc.), macromolecules (e.g., polysaccharides, hyaluronan, glycosaminoglycans—GAGs—and proteoglycans—PGs), and specialised soluble factors (e.g., ions, growth factor, cytokines, and hormones).

extracellular matrix cell-tissue interactions tissue engineering

1. Introduction

Degeneration or loss of organ and/or tissue function due to injury, disease, or ageing has a tremendous impact on quality of life and poses a large social and economic cost. Annually, billions of U.S. dollars are spent to perform surgical procedures to restore damaged tissues and organs. Therefore, in the last fifty years, new strategies have emerged to overcome these problems like Tissue Engineering (TE) and Regenerative Medicine (RM) [1]. These strategies promote the regeneration of damaged or diseased tissues and organs using the synergistic action of biomaterial-based scaffolds, growth factors, and cells [2]. It is essential to understand how tissues naturally recover when employing a TE approach, as well as the actors, mechanisms, and signals involved in processes that occur spontaneously in tissues [3]. This knowledge allows the design of scaffolds that best mimic the characteristics of the native tissue and therefore promotes new tissue formation or regeneration.
In tissues and organs, the extracellular matrix (ECM) is an essential extracellular element that surrounds cells, characterised by its sophisticated nanoarchitecture. It is a highly hydrated structure composed of cell-secreted proteins (e.g., collagen, fibronectin, elastin, etc.), macromolecules (e.g., polysaccharides, hyaluronan, glycosaminoglycans—GAGs—and proteoglycans—PGs), and specialised soluble factors (e.g., ions, growth factor, cytokines, and hormones) [4].
ECM provides structural and mechanical support in which cells can adhere and operate but, above all, it offers a broad spectrum of biophysical (e.g., stiffness, topography, viscoelasticity, etc.) and biochemical (e.g., receptor targeting ligands, pH, soluble signalling factors, etc.) cues that regulate vital cellular functions such as survival, adhesion, migration, proliferation, self-renewal, differentiation, morphogenesis, and gene expression [5]. In particular, cell expression of protein-receptors, like integrins, on their plasmatic membrane allows binding to the ECM and initiates a cascade of many cellular and tissue processes that influence regeneration. Therefore, understanding how cells interact with the ECM is crucial to obtain a biomaterial-based scaffold that allows cells to colonise and interact with the biomaterial as they naturally do with ECM, therefore leading to regeneration processes. TE scaffolds should evoke the native ECM, providing mechanical support and direct tissue development. To achieve this goal, the strategy is to design and manufacture scaffolds with specific characteristics and nanoarchitecture like native ECM, resulting in increased biological interactions between cells and biomaterial, thereby supporting cell infiltration, adhesion, differentiation, and oxygen and nutrient transport [6][7][8]. The two main functionalization approaches are bulk and surface functionalization. The tailoring of the biomaterial surface is of particular interest to improve interactions between cells/tissue and scaffolds. The surface is the scaffold’s part that is in direct contact with the human body so it is decisive for the performance and host acceptance of the scaffold [3]. Specific properties of biomaterials, such as hydrophilicity, free energy, roughness, softness, chemical composition, and morphology, influence cell–scaffold interactions and the success of the healing process. In recent years, many studies have focused on surface modifications for the development of biocompatible and bioactive biomaterial scaffolds without altering the bulk material properties [9], like the immobilisation of functional groups and active biomolecules, or permeability and mechanical properties modification.

2. ECM: A Key Player for TE

The ECM composition can vary among tissue types, resulting in several phenotypes that confer tissue specificity in physical and mechanical properties. In addition, ECM composition can be modified in response to intrinsic and extrinsic factors, giving rise to a dynamic and responsive niche for cells and tissues [10].

2.1. ECM Structure

The structural organisation of ECM includes two layers: the pericellular matrix and the interstitial matrix. The pericellular matrix is a well-organised network in close contact with the overlying cells by establishing cross-junctions with integrins, Discoidin Domain Receptors (DDRs), and peptidoglycans [11]. A classic example of a pericellular matrix is represented by the Basement Membrane (BM) [12], an adhesive microenvironment that provides biochemical and physical support to resident cells. Its main molecular components are collagen type IV, laminins, nidogen 1 and 2, and PGs such as perlecan, agrin, collagen type XV, and collagen type XVIII [11][13]. Epithelial cells (ECs) can adhere to BM thanks to specific structures called hemidesmosomes, formed by the interactions of cell surface integrins and intermediate filaments with laminins [11][14]. The interstitial matrix is generally more porous and less dense than the overlying BM. It is mainly composed of collagens, elastin, and fibronectin, creating a final 3D amorphous gel [12].

2.2. ECM Components

ECM composition can vary among tissue types and can be influenced by development stage, age, and pathology [5]. Its components are classified into (1) fibrillar, structural, and adhesive proteins (collagen, elastin, laminin, fibronectin, vitronectin); (2) amorphous matrix macromolecules (PGs, GAGs, hyaluronan); and (3) specialised soluble factors (growth factors, cytokines, hormones) [5].
Collagens are the most abundant components in the ECM. They are synthesised mainly by fibroblasts, representing up to 30% of the total proteins in humans, creating a 3D network of fibres in both pericellular and interstitial matrices [11]. Twenty-eight different collagen types are responsible for creating a 3D network of fibres in the pericellular and interstitial matrix [15]. Collagens are classified into seven types: types I, II, III, V, XI, XXVI, and XXVII are the most abundant among tissues and they maintain a fibrillar organisation, whereas types IV, VIII, and X form networks and supramolecular structures by interacting with other ECM components [15]. Collagens are often exploited in TE to create collagen-based biomaterials to be used in sports medicine and wound healing [16]; however, the role of collagens in the ECM for physiological and pathological tissue conditions is still being studied [17]. Elastin is an adhesive component of the ECM found in specific tissue types, where it is responsible for adequate tissue elasticity [15] and tissue stretching recovery [12]. It is constituted by tropoelastin monomers that interact by self-assembling to finally obtain mature elastic fibres, and then they cross-link with an outer layer of fibrillin microfibrils, creating an elastic fibre [12]. Laminins are a class of heterotrimeric cross-shaped glycoproteins localised in the BM [11][12]. Besides being crucial during embryonic development, laminins play a role in cellular processes like differentiation, migration, and adhesion, ensuring the survival of tissues [11]. Fibronectin (FN) is localised in the BM, and it is responsible for cellular adhesion and wound healing processes [12][18]. It can exist in two different forms: the soluble plasmatic form is in the blood to be delivered to the site of injury, and the cellular form is synthesised by fibroblasts [12]. Cells can assemble FN by taking soluble molecules from the blood or synthesising it autonomously. FN fibrils can interact with the actin cytoskeleton of cells through a class of surface receptors called integrins, finally forming fibrils with a thickness between 10 and 100 nm [12]. Vitronectin (VNT), also known as S-protein or serum diffusion factor, is an adhesive glycoprotein that is located between cells and the ECM, where it interacts with several ligands like integrins, plasminogen activator inhibitor-1 (PAI-1), and the urokinase plasminogen activator receptor (uPAR) [19]. VNT works as a multimeric complex (unfolded or active form) in the ECM of several tissue types [19], where it promotes ECs adhesion and tissue remodelling [20]. Dysfunction and misfolding of VNT can promote the development of neurodegenerative diseases, such as age-related macular degeneration, Alzheimer’s disease, and multiple sclerosis, showing the essential role played by the ECM [20].
GAGs are polar carbohydrates composed of repeating disaccharide units of N-acetylated hexosamines (N-acetyl-d-galactosamine or N-acetyl-d-glucosamine) and d-/l-hexuronic acid (d-glucuronic acid or l-iduronic acid) [11]. GAGs are divided into four groups based on their carbohydrate residues: hyaluronic acid (HA), chondroitin sulfate (CS) and dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) [5]. HA is a linear GAG made by repeating disaccharide units of d-glucuronic acid and N-acetyl-d-glucosamine found in the ECM with or without a protein core. HA is a major constituent of the pericellular matrix where it can adsorb substantial amounts of water molecules by affecting tissue elasticity [11]. In mammals, there are three HA synthase (HAS) isoforms responsible for HA synthesis, whereas for hyaluronidases degrade HA, the combination of these two enzymatic activities could affect HA size and molecular weight [11]. GAGs interact with core proteins to finally form PGs, which are localised not only in the ECM, but also in intracellular compartments and at the cell surface, influencing some cellular processes like proliferation, migration, differentiation, apoptosis, and adhesion. The PGs interactions with growth factors, cytokines, and cell surface receptors, either via their core proteins or through their GAGs, are essential for the formation of an ECM 3D scaffold [11]. PGs can be classified into four families: intracellular, cell surface, pericellular, and extracellular membrane. Extracellular PGs are the most abundant and they are divided into two subgroups: hyalectans, which include aggrecan, versican, neurocan, and brevican; small leucine-rich PGs, like decorin, are the largest family of PGs containing eighteen members divided into five classes ubiquitously expressed in most ECMs [11]. Pericellular PGs, like perlecan and agrin, are often associated with cells through integrin cell receptors. Syndecans and glypicans are the two main subfamilies of cell surface PGs that link ECM components with the cellular surface [11]. Serglycin is the only characterised intracellular PG, and it is present not only in hematopoietic cells, where it manages the storage and the packaging of bioactive molecules, but also in ECs and smooth muscle cells, chondrocytes, fibroblasts, and tumour cells, modulating their aggressiveness [11].
Growth factors, cytokines, and hormones localised in the ECM can modulate cellular functions through biochemical interactions. The specific growth factors present in the ECM can be different among tissue types and for physiological and pathological conditions. However, one of the most common growth factors is represented by the Transforming Growth Factor-β (TGF-β), a family of homodimeric or heterodimeric secreted cytokines. These proteins are synthesised in a native form that is cleaved during the secretory pathway, leading to the formation of a mature dimeric ligand bounded via a single disulfide bond [21][22]. TGF-β is stored in the matrix together with the latent TGF-β binding protein (LTBP) in an inactive form. Once it is activated, it can regulate ECM remodelling and it can promote a fibroblast to myofibroblast transition, which is essential to induce the fibrotic process [23]. Some ECM macromolecules can directly bind soluble factors, for example, decorin binds TGF-β, modulating its bioavailability, but also vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-I), and platelet-derived growth factor (PDGF) [24]. Parallelly, FN shows some binding sites for epidermal growth factor (EGF), VEGF, and hepatocyte growth factor (HGF), modulating the migration and metabolism of ECs [25].

2.3. Cellular Adhesion to the ECM

The interactions between ECM and adherent cells are mediated by a family of transmembrane proteins called integrins. In addition to ensuring cell anchorage to the matrix and making contact by binding FN, laminin, collagen, and cellular receptors, they also provide cell–cell interactions [26]. Integrins are heterodimers of α and β subunits. Humans express eighteen α and eight β subunits that, when combined, can generate twenty-four different integrin heterodimers with overlapping but non-redundant functions [26]. The integrins’ activation requires some structural rearrangements to modulate the affinity for ligands, like the activation of the proteins talin and kindlin, and the negative regulators ICAP-1α and filamin [27]. The balance between activated and inactivated integrins controls cell adhesion and polarity. In certain classes of ECs, a complex called hemidesmosome, which includes α6β4 integrins, serves as a linkage between intermediate filaments and adherent cells. In addition, a second major bond between ECs and the underlying BM is represented by integrins-containing focal adhesions that, unlike hemidesmosomes, connect the actin cytoskeleton to the BM through indirect integrin–actin connections [26][28]. Focal adhesions also mediate some transduction pathways like cytoplasmic alkalinization, can increase intracellular calcium, activate tyrosine kinases, protein tyrosine phosphatases, and lipid kinases, and modulate gene expression [6].
Although integrins are the most studied, ECM possesses other families of macromolecule receptors including the DDR family for collagens, CD44 and Receptor for HA-Mediated Motility (RHAMM) for HA, and HS PG-like syndecans for various other ECM molecules [25]. The DDR family includes DDR1 and DDR2, whose ligands are collagen I–III, while DDR1 can only recognise collagen IV [29]. The main CD44 ligand is HA, but also osteopontin [30][31]. Syndecans’ ligands are collagen I, III, and V, FN, and laminin, and can also interact with other integrins and cell adhesion receptors [32].

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Subjects: Cell & Tissue Engineering; Materials Science, Biomaterials
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Paola Nitti
,
Athira Narayanan
,
Rebecca Pellegrino
,
Stefania Villani
,
Marta Madaghiele
,
Christian Demitri
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Revisions: 2 times (View History)
Update Date: 09 Oct 2023
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