Extracellular Matrix Replacement is a non-cellular structure that regulates the function, structure, and communication of cells and tissue through a network of macromolecules.

The highly dynamic structural network of the extracellular matrix continuously undergoes changes mediated by various matrix-degrading enzymes during pathological and normal conditions. Interactions of the cell-extracellular matrix are facilitated mainly by heterodimer molecules and are very important to the structure of the tissue.

Deregulation of extracellular matrix structure and composition is associated with the progression and development of many pathologic and psychological conditions. Therefore, it is important to understand the function and structure of the extracellular matrix as well as its role in wound healing and neuronal regeneration in the PNS (peripheral nervous system) and CNS (central nervous system).

What is the function and structure of the extracellular matrix?

ECM (extracellular matrix) comprises of non-cellular constituents that form a scaffold for the cellular components within tissues. Its structure is essentially made up of fibers, proteoglycans, collagen, and multi adhesive proteins.

The main functions of the ECM include:

• Facilitating communication between cells
• Forming a support structure for cells
• Regulating essential cell processes such as differentiation, migration, and growth
• Segregating tissues
• Tissue repair

There are two main types of extracellular matrices, each with a different structure;

• interstitial matrices and
• pericellular matrices.

Interstitial matrices surround cells whereas the pericellular matrices are cell-associated.

The basement membrane which is found between the connective and functional tissue is a good example of pericellular matrices. The structure of the basement membrane provides an important anchoring layer that ensures functional cells are kept together. Cells within the extracellular matrix communicate through integrate signals and surface receptors that are associated with their specific function.

Moreover, cells play a critical role in the formation of the ECM through the secretion of multi adhesive proteins and matrix macromolecules. Therefore, differences in the extracellular matrix structure influence the biomechanical practices of the entire network as well as signals that determine cell response.

What is the relationship between the extracellular matrix and diabetes?

Diabetic neuropathy is one of the serious complications of diabetes. Morphological changes are caused by changes in the extracellular matrix. Therefore, basement membranes thicken and the tubulointerstitial space and the glomerular mesangial matrix are expanded as a result of increased amounts of the extracellular matrix.

In diabetic neuropathy, the proteoglycans in the extracellular matrix exhibit a complex pattern of changes. The proteoglycan in the tubulointerstitial space and the mesangium are increased but decreased in the basement membranes. There are also significant changes in the structures and amounts of heparan sulfate chains.

Such changes affect growth factors that regulate cell-extracellular matrix synthesis and growth factors, whereas cell attachment affects podocytes and endothelial cells.

Enzymes that modulate heparan sulfate structures, including sulfatases and heparanase, are implicated in diabetic neuropathy. Other enzymes also modulate proteoglycans and extracellular matrix proteins, such as serine proteases and metalloproteinases, as well as their inhibitors.

In diabetic neuropathy, changes in the levels of these enzyme classes and their corresponding inhibitors are seen in the kidneys and plasma. Signaling pathways, hyperglycemia, and several growth factors affect extracellular matrix synthesis and turn over in diabetic neuropathy. Whether extracellular matrix components can be effectively used to detect early kidney changes is a very important research topic.

One of the key elements in diabetic neuropathy is changes in the ECM of several components in the kidneys. Therefore, changes seen in the extracellular matrix are critical in diagnostics as well as therapeutic and prognostic purposes.

Tissue Regeneration

The extracellular matrix is the main factor necessary in the process of creating new tissue and networks. Many different factors trigger the growth of extracellular matrix or help form a synthetic extracellular matrix. Currently, extracellular matrix replacement is involved in many mechanisms including wound healing and neurological regeneration capacity associated with neurodegenerative and/or pathological disease.

The wound healing process is largely influenced by the proliferation and migration of fibroblasts in the site of injury. Fibroblast is a part of the extracellular matrix and it determines wound healing outcome. Fibroblasts produce collagen that links to the wound and it also affects the reepithelialization process that closes the wound. During proliferation, fibroblasts produce type III collagen and aid in wound closure.

An important part of the tissues’ holding capacity is the extracellular area which is mainly occupied by the extracellular matrix. Even though the extracellular matrix mainly consists of collagen, the composition varies depending on the ground or developing molecules. However, the extracellular matrix is composed of three main classes of biomolecules. Proteoglycans, linked to glycosaminoglycans and fibrous protein (collagen, laminin, vitronectin, elastin, and fibronectin).

Some of the most important constituents of connective tissue, which is mainly composed of the extracellular matrix, are ground substance and fibroblasts. Ground substance is an integration complex between proteoglycans, glycosaminoglycans, and glycoproteins (mainly fibronectin and laminin). Fibroblasts secrete the matrix constituents in most connective tissues. However, in some specialized connective tissues, like bone and cartilage, matrix components are secreted by osteoblasts and chondroblasts.

In general, each cell needs to attach to the ECM (extracellular matrix) in order to multiply and grow. The extracellular matrix is mainly responsible for providing anchorage and support for the shape of cells, regulating and determining cell behavior and dynamics including cell adhesion, cell survival, cell polarity, cell migration, and cell proliferation. Moreover, the extracellular matrix is involved in the regenerative and growth mechanism, healing process, and it also provides mechanical support for tissues.

The bottom-line

In clinical applications, many different factors that trigger the growth and development of the extracellular matrix are being used to create a synthetic extracellular matrix.

In addition to being involved in wound healing, it is also possible to use scaffold by acellular nerve allografting, a chemical decellularization process, to maintain most of the extracellular components and eliminate antigens that may cause allograft rejection, which effectively guides and enhances nerve regeneration.

In tissue engineering, extracellular matrix replacement and development has been used as a scaffold to enhance direct axonal growth, especially on peripheral nerve injury, as is common in diabetic neuropathy.