**2. The structure and function of extracellular matrix**

An essential part of the holding capacity of tissues is the extracellular area. The extracellular region is primarily occupied by a complicated network of macromolecules constituent called as extracellular matrix (ECM). The composition of ECM is varied, depends on the species and also developing or ground molecules (**Figures 1** and **2**). Commonly, the ECM is composed of three major classes of biomolecules; there are glycosaminoglycans (GAGs), linked to a protein known as the proteoglycans, and also fibrous proteins, including collagen, elastin, fibronectin, vitronectin, and laminin.

In addition, connective tissue (**Figure 3**) is also composed of the matrix of ECM. One of the essential components of connective tissue is fibroblasts and ground substance. Ground substance is a mixing complex between GAGs, proteoglycans, and glycoproteins (mainly laminin and fibronectin). In most connective tissues, the matrix constituents are secreted by fibroblasts, but in several certain specialized types of connective tissues, like cartilage and bone, these components are secreted by chondroblasts and osteoblasts (**Table 1**).

In general, all the cells need to attach to the extracellular matrix to grow and multiply. Extracellular matrix provides support and anchorage for the shape of the cells, regulates and determines cells dynamic and behavior including cell survival, cell proliferation, cell polarity, cell differentiation, cell adhesion, and cell migration. Moreover, the ECM, also gives the mechanical support for tissues and is involved in the growth mechanism, regenerative, and healing processes.

this polysaccharide, one of the two sugars in a repetitive disaccharide is always an amino sugar such as N-acetylglucosamine or N-acetylgalactosamine [3]. The second sugar of GAGs usually is the uronic acid like glucuronic or iduronate. GAG molecules are negatively charged, because there are sulfate or carboxyl groups in most of the sugar. The five main groups of GAGs are differentiated based on the sugar type including (1) hyaluronan or hyaluronic acid, (2) chondroitin sulfate, (3) dermatan sulfate, (4) heparan sulfate, and (5) keratin sulfate. Hyaluronan is the simplest GAGs. Hyaluronan does not contain sulfate sugars; all disaccharides units are the same, and the chain length is extensively big (thousands of sugar monomers). The hyaluronan

**Figure 3.** The components of connective tissue. In addition to the extracellular matrix, connective tissues are characterized by a lot of cells, mainly the fibroblasts, all of which are surrounded by the ground substance. Modified from Mescher [2]. *Source:* Michael W. King: Integrative Medical Biochemistry Examination and Board Review, www.accesspharmacy.com

Copyright © McGraw-Hill Education. All rights reserved.

**Figure 2.** The extracellular matrix of hyaline cartilage found in abundant collagen fibril and proteoglycan aggregates. The chemical analysis of the ground substance reveals that it contains a few glycoproteins and a high concentration of three types of glycosaminoglycans: hyaluronic acid, chondroitin sulfate, and keratan sulfate. Adapted from Crammer and Bakkum [1].

The Role of Extracellular Matrix in Tissue Regeneration http://dx.doi.org/10.5772/intechopen.75728 67

#### **2.1. Glycosaminoglycan (GAGs)**

GAGs are unbranched chains of polysaccharides; GAGs are composed of repeating disaccharide units and are heterogeneous groups in negatively charged polysaccharide chains that are covalently linked to proteins to form proteoglycan molecules. The name GAGs is because in

**Figure 1.** The structure of the extracellular matrix. The ECM mainly contained collagen fibers. There are also some glycoproteins as an adhesion molecule, such as integrin family fibronectin and laminin, which conduct cell attachments to the ECM by binding to collagen in the ECM and integrin. The intracellular part of integrin highly associated with the cytoskeleton thus may promote to anchoring the cell. In the end, there are various proteoglycans in the ECM that act as primary proteins and are profoundly modified by the addition of sugars.

**2. The structure and function of extracellular matrix**

tin, vitronectin, and laminin.

66 Tissue Regeneration

**2.1. Glycosaminoglycan (GAGs)**

An essential part of the holding capacity of tissues is the extracellular area. The extracellular region is primarily occupied by a complicated network of macromolecules constituent called as extracellular matrix (ECM). The composition of ECM is varied, depends on the species and also developing or ground molecules (**Figures 1** and **2**). Commonly, the ECM is composed of three major classes of biomolecules; there are glycosaminoglycans (GAGs), linked to a protein known as the proteoglycans, and also fibrous proteins, including collagen, elastin, fibronec-

In addition, connective tissue (**Figure 3**) is also composed of the matrix of ECM. One of the essential components of connective tissue is fibroblasts and ground substance. Ground substance is a mixing complex between GAGs, proteoglycans, and glycoproteins (mainly laminin and fibronectin). In most connective tissues, the matrix constituents are secreted by fibroblasts, but in several certain specialized types of connective tissues, like cartilage and bone,

In general, all the cells need to attach to the extracellular matrix to grow and multiply. Extracellular matrix provides support and anchorage for the shape of the cells, regulates and determines cells dynamic and behavior including cell survival, cell proliferation, cell polarity, cell differentiation, cell adhesion, and cell migration. Moreover, the ECM, also gives the mechanical support for tis-

GAGs are unbranched chains of polysaccharides; GAGs are composed of repeating disaccharide units and are heterogeneous groups in negatively charged polysaccharide chains that are covalently linked to proteins to form proteoglycan molecules. The name GAGs is because in

**Figure 1.** The structure of the extracellular matrix. The ECM mainly contained collagen fibers. There are also some glycoproteins as an adhesion molecule, such as integrin family fibronectin and laminin, which conduct cell attachments to the ECM by binding to collagen in the ECM and integrin. The intracellular part of integrin highly associated with the cytoskeleton thus may promote to anchoring the cell. In the end, there are various proteoglycans in the ECM that act as

primary proteins and are profoundly modified by the addition of sugars.

these components are secreted by chondroblasts and osteoblasts (**Table 1**).

sues and is involved in the growth mechanism, regenerative, and healing processes.

**Figure 2.** The extracellular matrix of hyaline cartilage found in abundant collagen fibril and proteoglycan aggregates. The chemical analysis of the ground substance reveals that it contains a few glycoproteins and a high concentration of three types of glycosaminoglycans: hyaluronic acid, chondroitin sulfate, and keratan sulfate. Adapted from Crammer and Bakkum [1].

this polysaccharide, one of the two sugars in a repetitive disaccharide is always an amino sugar such as N-acetylglucosamine or N-acetylgalactosamine [3]. The second sugar of GAGs usually is the uronic acid like glucuronic or iduronate. GAG molecules are negatively charged, because there are sulfate or carboxyl groups in most of the sugar. The five main groups of GAGs are differentiated based on the sugar type including (1) hyaluronan or hyaluronic acid, (2) chondroitin sulfate, (3) dermatan sulfate, (4) heparan sulfate, and (5) keratin sulfate. Hyaluronan is the simplest GAGs. Hyaluronan does not contain sulfate sugars; all disaccharides units are the same, and the chain length is extensively big (thousands of sugar monomers). The hyaluronan

**Figure 3.** The components of connective tissue. In addition to the extracellular matrix, connective tissues are characterized by a lot of cells, mainly the fibroblasts, all of which are surrounded by the ground substance. Modified from Mescher [2]. *Source:* Michael W. King: Integrative Medical Biochemistry Examination and Board Review, www.accesspharmacy.com Copyright © McGraw-Hill Education. All rights reserved.


Modified from Crammer and Bakkum [1].

**Table 1.** The cells of connective tissue.

is not connected covalently to some core proteins. Proteoglycans are composed of GAG chains that are covalently linked to the core protein and considered to have a significant role in chemical signaling among cells (**Figure 4**).

dimer composed of two nearly identical ~250 kDa subunits linked covalently near the Cterminal by a pair of disulfide bonds at one end side. Fibronectin is a ligand member of the integrin receptor family. Integrins are structurally and functionally related to the cell surface

**Figure 4.** The structure of glycosaminoglycan (A) structure of a proteoglycan monomer. Several glycosaminoglycan chains (chondroitin sulfphate and keratan sulfate) attached to a core protein. The protein molecule can connect to a long hyaluronic acid molecule to help form a proteoglycan aggregate. (B) An example of an individual glycosaminoglycan chain, in this case, chondroitin 6-sulphate, and its attachment to the core protein. (C) The morphological of a proteoglycan monomer. (A and B) Adapted from courtesy Dino Juarez, National University of health sciences; (C) Adapted from

The Role of Extracellular Matrix in Tissue Regeneration http://dx.doi.org/10.5772/intechopen.75728 69

The primary type of fibronectin is known as type III fibronectin replica (cylinder), which binds to integrins. This model has a length of about 90 amino acids. Fibronectin appears in a soluble and fibrillar form. There are two others fibronectin isoforms, which are fibronectin type I (hexagon) and fibronectin type II (square) [6]. Fibronectin is not only crucial for attaching cells to matrices but also to guiding cell migration in vertebrate embryos. Fibronectin has many functions, which allow it to interact with many extracellular substances, such as colla-

Extracellular matrix is the primary factor required in the process of forming a new network and tissue. Along with the development found, many different factors can trigger the growth of ECM or used to create a synthetic ECM. Currently, ECM is involved in various mechanisms such as wound healing with or without the involvement of mesenchymal conditioned medium and neuronal regeneration capability associated with pathologic and/or neurode-

as heterodimeric receptors that link the ECM with the intracellular cytoskeleton.

gen, fibrin and heparin, and with specific membrane receptors in responsive cells.

**3. Tissue regeneration**

Crammer and Bakkum [1].

generative disease.

#### **2.2. Collagen**

Collagen is a major abundant fibrous protein in the extracellular matrix. Collagens, which constitute the primary structural element of the ECM, provide tensile strength, regulate cell adhesion, support chemotaxis and migration, and direct tissue development [4]. Recently, there have been already described 28 types of collagen. The main types of collagen found in connective tissues are types I, II, III, V, and XI.

Collagen polypeptide chains are synthesized on membrane-bound ribosomes and fed into the lumen of the endoplasmic reticulum as large precursors, called the pro-α chains. Each pro-α chain then joins the other two to form a hydrogen-bond, triple-stranded hydrogen molecule known as a procollagen. After secretion, the fibrillar procollagen molecule divides to become collagen molecules, which converge into fibrils [5].

#### **2.3. Fibronectin**

Fibronectin is an extracellular protein that makes cells adhere to the matrix. Fibronectin is considered as a large glycoprotein found in all vertebrates. Fibronectin usually exists as a

**Figure 4.** The structure of glycosaminoglycan (A) structure of a proteoglycan monomer. Several glycosaminoglycan chains (chondroitin sulfphate and keratan sulfate) attached to a core protein. The protein molecule can connect to a long hyaluronic acid molecule to help form a proteoglycan aggregate. (B) An example of an individual glycosaminoglycan chain, in this case, chondroitin 6-sulphate, and its attachment to the core protein. (C) The morphological of a proteoglycan monomer. (A and B) Adapted from courtesy Dino Juarez, National University of health sciences; (C) Adapted from Crammer and Bakkum [1].

dimer composed of two nearly identical ~250 kDa subunits linked covalently near the Cterminal by a pair of disulfide bonds at one end side. Fibronectin is a ligand member of the integrin receptor family. Integrins are structurally and functionally related to the cell surface as heterodimeric receptors that link the ECM with the intracellular cytoskeleton.

The primary type of fibronectin is known as type III fibronectin replica (cylinder), which binds to integrins. This model has a length of about 90 amino acids. Fibronectin appears in a soluble and fibrillar form. There are two others fibronectin isoforms, which are fibronectin type I (hexagon) and fibronectin type II (square) [6]. Fibronectin is not only crucial for attaching cells to matrices but also to guiding cell migration in vertebrate embryos. Fibronectin has many functions, which allow it to interact with many extracellular substances, such as collagen, fibrin and heparin, and with specific membrane receptors in responsive cells.
