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 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. 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. 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. After secretion, the fibrillar procollagen molecule divides to become collagen molecules, which converge into fibrils [ 5 ]. Fibronectin is an extracellular protein that makes cells adhere to the matrix. Fibronectin is considered as a large glycoprotein found in all vertebrates. 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. 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.
The process of wound healing is strongly influenced by the role of migration and proliferation of fibroblasts in the injury site. Indeed fibroblast is one part of ECM. The proliferation of fibroblasts determines the outcome of wound healing.
Fibroblasts will produce collagen that will link to the wound, and fibroblasts will also affect the process of reepithelialization that will close the wound. Fibroblasts will produce type III collagen during proliferation and facilitate wound closure. During proliferation stage, fibroblasts proliferation activity is higher due to the presence of TGF-stimulated fibroblasts to secrete bFGF.
The higher number of fibroblasts also induces increasing of collagen synthesis. Collagen fiber is the major protein secreted by fibroblast, composed of extracellular matrix to replace wound tissue strength and function. Collagen fibers deposition was significant on 8—10 days after injury. The number of fibroblasts increases significantly, in correlation with the presence of an abundance of bFGF on 8—10 days after wounding. Mesenchymal stem cell conditioned medium MSCM can be defined as secreted factor that referred to as secretome, microvesicle, or exosome without the stem cells which may found in the medium where the stem cells are growing.
The use of MSCM as cell-free therapy has more significant advantages in comparison to the use of stem cells, mainly to avoid the need of HLA matching between donor and recipient as a consequence to decrease the chance of transplant rejection. Additionally, MSCM is more easy to produce and save in large quantity. Recently, it has been mentioned that widespread neuronal cell death in the neocortex and hippocampus is an ineluctable concomitant of brain aging caused by diseases and injuries.
However, recent studies suggest that neuron death also occurs in functional aging and it seems in related to an impairment of neocortical and hippocampal functions during aging processes. Data from WHO and Alzheimer report show increasing number of people suffering from dementia along with aging. Profoundly understanding the role of extracellular matrix ECM in influencing neurogenesis has presented novel strategies for tissue regeneration Figure 5.
Microscopic anatomy of the extracellular matrix within the central nervous system CNS. The three major compartments of the extracellular matrix in the CNS are the basement membrane, perineuronal net, and neuronal interstitial matrix. The basement membrane is found surrounding cerebral blood vessels, the perineuronal net is a dense matrix immediately surrounding neuronal cell bodies and dendrites, and the neuronal interstitial matrix occupies the space between neurons and glial cells.
Adapted from Lau et al. Within this glial scar, upregulated proteoglycans like CSPGs and changes in sulfation patterns within the ECM result in the building of regeneration inhibition [ 10 ]. To solve the problem, some manipulation on the intrinsic extracellular matrix by using traditional herb such as Ocimum sanctum extract was already done. In the in vivo and in vitro model using human brain microvascular endothelial cells HBMECs which mimics blood-brain barrier, the treatment of the extract may promote the cell proliferation on the hippocampus area and HBMECs in the condition upregulation of choline acetyltransferase ChAT enzyme [ 11 , 12 ].
In addition, there is also a chance to use nanometer-sized scaffolds in the presence of other substrates such as vascular endothelial growth factor or hyaluronic acid with laminin. This scaffold may conduct a way to the regenerative capacity and functional recovery of the CNS to reconstruct formed cavities and reconnect neuronal processes.
Thus, the artificial scaffold functions to enhance the communication between cells, allowing for improvement in proliferation, migration, and differentiation [ 13 , 14 , 15 ]. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting that eliminates the antigens responsible for allograft rejection and maintains most of the ECM components, which can effectively guide and enhance nerve regeneration.
In the field of tissue engineering by an in vivo model, a lot of successful carriers and matrices have been employed as a scaffold to promote direct axonal growth on peripheral nerve injury [ 16 ].
In conclusion, the 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 that can trigger the growth of ECM are used to create a synthetic ECM.
Recently, 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 neurodegenerative disease. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting to eliminate the antigens responsible for allograft rejection and maintain most of the ECM components, which can effectively guide and enhance nerve regeneration.
In the field of tissue engineering by an in vivo model, significant progress on matrices development have been utilized as a scaffold to promote direct axonal growth on peripheral nerve injury. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.
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Correspondence to Stina Oredsson. FJ has the following competing financial interest: co-founder, shareholder, and consultant of the private company, Cellevate AB, Lund, Sweden, fabricating the 3D scaffolds. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
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Download PDF. Subjects Breast cancer Cancer Cancer models. Abstract The appreciation that cell interactions in tissues is dependent on their three dimensional 3D distribution has stimulated the development of 3D cell culture models. Introduction The extracellular matrix ECM is the non-cellular network of various structural and adhesive macromolecules that are essential for many fundamental cellular processes 1.
Collection of cell culture medium and cell extracts At the time of medium change on days 3, 7, 10, and 14 after seeding, the old cell culture medium was collected for IL-6 analysis. Decellularization and fixation Following medium collection on days 3, 7, 10, and 14 after seeding, the 3D scaffolds were washed three times with sterile PBS. Immunofluorescence staining The ECM of the decellularized samples was stained for visualization of laminin, fibronectin, or collagen I separately.
Confocal laser scanning microscopy For visualization of cell and ECM distribution in 3D scaffolds, stained samples were mounted with RapiClear 1. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Figure Discussion The traditional perspectives of cancer biology have shifted from the study of mainly cancer cells to include the stromal cells as well as the ECM Conclusions We have constructed an artificial 3D human tumour which in many aspects resemble a human tumour in the body.
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