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EXTRACELLULAR MATRIX

EXTRACELLULAR MATRIX (ECM)

The extracellular matrix (ECM) is a complex network that acts like a scaffold, providing structural support for cellular constituents and is crucial for maintaining tissue homoeostasis. The ECM is composed of around thousand proteins, including collagens, glycoproteins (GP), and ECM-associated proteins, which show diversity of biochemical and biophysical functions. The ECM is a dynamic structure and continuously undergoes controlled remodelling, manifested by deposition, modification, and degradation of all its components. Aging is characterised by progressive functional decline of tissue over time that leading to deterioration and ECM dysfunction. All the changes that occur during aging, influence the composition of the ECM, contributing to its dysregulated behaviour. Fibroblasts are main producers of ECM and in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. Various triggers can lead cells to enter into senescence, including DNA replication stress, telomere dysfunction, oxidative stress. Senescent cells negatively impact ECM regeneration while creating a pro-inflammatory environment due to the senescence-associated secretory phenotype (SASP), that may have a detrimental role in promoting ECM damage and aging. Senescent fibroblasts paracrine effect, is related to the fact that they can produce a variety of secreted factors, such as cytokines, growth factors, and proteases. These secreted pro-inflammatory components, can promote age-related fibrosis and many other unfavorable aberrant matrix remodelling, ultimately leading to a functional decline of ECM. 

STRUCTURAL COMPONENTS  

COLLAGEN

Collagen has an essential role in providing tensile strength to the ECM. Collagen monomer is a triple helix molecule, which is composed of three α chains made of a repetitious amino acid sequence requiring glycine as every third residue and often have a high amino acid (proline and hydroxyproline) content. Collagens assemble into hierarchical structures, forming fibrils and although 28 types of collagen have been identified, collagens I and III, respectively compose approximately 90% and 10% of the total collagen in the ECM.Furthermore collagen plays a fundamental role in intracellular signal transduction, regulating cell adhesion, support chemotaxis and migration and direct ECM development. 

GLYCOSAMINOGLYCANS (GAGs) AND PROTEOGLYCANS (PGs) 

They are abundant structural components of the extracellular matrix in addition to collagen fibers. GAGs are long, linear polysaccharides including hyaluronic acid and other substances like chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate. Proteoglycans are composed of glycosaminoglycan chains that are covalently attached to a protein core. Hyaluronic acid forms proteoglycan aggregates, which are large complexes of HA and HA-binding PGs. Their crosslinking to other matrix proteins, mainly the collagen network, results in the formation of supermolecular structures, involved in key processes, increasing ECM stiffness and stability, acting to present cytokines to their cognate receptors, acting as co-receptors for growth factor receptors (GF-R), potentiating GF-R signaling, enhancing autocrine receptor signaling and clustering, regulating the ECM water retenion and the collagen fibril assembly, interacting with the membrane-bound receptors, CD44,  moduulating dermal fibrogenesis, collagenolysis and ECM remodeling. GAG creates a signaling networks that modulate cytokines and growth factors, as well as cell/matrix interaction proteins including collagen. 

GLYCOPROTEINS (GP)

Glycoproteins (GP) participate in ECM structural formation, in ECM–cell interactions, and retain different growth factors that can be activated by present remodeling enzymes.

Fibronectin 

Fibronectin (FN) has an important role in many cell functions as cell adhesion, migration, growth, and differentiation. FN mediates intracellular signaling through interaction with integrin receptors or syndecans located on the cell surface. 

Laminin 

They are major structural component of the basement membrane, and are essential to its proper function. Laminins play important roles in ECM morphogenesis and homeostasis by regulating cell adhesion, migration, proliferation and matrix-mediated signaling, using several specific surface receptors.   

Elastin  

Elastin has a central role in providing tensile strength, firmness, and suppleness of ECM, which are essential for its proper functions.

Thrombospondin 1

Thrombospondins (TSPs) are represented by a family of matricellular proteins They take a part in processes such guiding extracellular matrix synthesis and remodeling and in inflammatory response, platelet aggregation, and angiogenesis. TSPs promotes collagen fibril assembly and interact with collagen through an adhesion site (MIDAS). These interactions are critical for normal tissue homeostasis.  

ECM-ASSOCIATED PROTEINS 

ECM-associated proteins play theirs role providing multiple inputs into cells to control survival, proliferation and motility of cells. They include proteases, or cross-linking enzymes, growth factors and different secreted factors.  

CCN Family

The CCN proteins are secreted in ECM exerting their action in a  wide range of biological processes such as proliferation, adhesion, migration, apoptosis, ECM production. They have a regulatory role in production of collagen and in its degradation, through regulation of protease expression. 

Matrix metalloproteinases MMPs

Matrix metalloproteinases are a family of enzymes called endoproteinases that have the ability irreversibly degrade the ECM components and activate cytokines, chemokines, and other ECM-associated proteins. In healthy tissues, MMP are tightly regulated at different levels, but In pathological conditions such inflammation and aging, MMPs dysregulation is observed at all the levels.  

ADAMs and ADAMTSs

A disintegrin and metalloproteinases transmembrane (ADAMs) and secreted ADAMs thrombospondin motifs (ADAMTSs) are enzymes that share the metalloproteinase domain with MMPs. ADAMs.  Their functions are important in many biological processes such as cell fate determination, migration, proliferation, angiogenesis, collagen processing and matrix proteoglycans cleavage. They are important in tissue development and maintenance.  

Tissue inhibitors of metalloproteinases TIMPs

Tissue inhibitors of metalloproteinases (TIMPs), as suggested by their name, are a family of endogenous inhibitors of MMPs and play an important role in the regulation of ECM turnover. Nonetheless, they also participate in modulation of cell growth.

 

 

 

HYALURONIC ACID (HA)

Hyaluronic acid (HA;Hyaluronan), is a nonsulfated linear glycosaminoglycan (GAG) polymer, composed of repeating units of glucuronic acid and N-acetylglucosamine, connected by β-linkages. HA is a central component of the ECM, living them viscosity and hydration. HA is not only a structural component of ECM but also an active, signaling molecule that serves several functions, such as basic structure, receptor protein  attachment, and cell-to-cell crosstalk. Hyaluronan is capable of contain up to 10,000 times its weight of water, generating the formation of loose and elastic matrices, facilitating and regulating cellular migration. Hyaluronan turnover is tightly regulated for the maintenance of tissue homeostasis, and ~30% of HA is replaced by newly formed HA per 24 h, resulting in balanced amounts of hyaluronan. In fact, of the estimated 15 g of HA in a person, about a third is turned over every day in situ, thus the complete turnover of hyaluronan is about 2 days, which is rapid compared with other ECM molecules, the majority of which have turnover times of over several weeks or longer. Furthermore, a significant part of HA, is drained via the lymph system into the blood, to be removed by liver. Probably, hyaluronan metabolism is so active in the ECM, due the intrinsic ability of hyaluronan to act as a scavenger of ROS and free radicals, by contributing to their elimination. Hyaluronan is synthesized by the action of hyaluronan synthases and is degraded by hyaluronidase,oxidative stress and mechanical forces and this creates a continuum of different-sized HA fragments, wich may range from several oligosaccharides to molecules of over 1 million Daltons in size. Different sizes of HA have different biological properties, compared with the full size and changes in the size distribution of HA in the ECM, are able to induce cell-signaling pathways, that are crucial for fundamental cellular functions. This is because of differences in the binding mode between high and low molecular mass hyaluronan on specific cell signal-transducing receptors, such as CD44). Smaller HA fragments can bind to CD44 and stimulates downstream TGFβ (Transforming Growth Factor β) pathways and promotes fibroblast to myofibroblast conversion, resulting in enhanced collagen synthesis and balanced ECM remodeling.