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Shnayder, N. Extracellular Matrix in Skin Wound Healing. Encyclopedia. Available online: https://encyclopedia.pub/entry/17459 (accessed on 27 July 2024).
Shnayder N. Extracellular Matrix in Skin Wound Healing. Encyclopedia. Available at: https://encyclopedia.pub/entry/17459. Accessed July 27, 2024.
Shnayder, Natalia. "Extracellular Matrix in Skin Wound Healing" Encyclopedia, https://encyclopedia.pub/entry/17459 (accessed July 27, 2024).
Shnayder, N. (2021, December 22). Extracellular Matrix in Skin Wound Healing. In Encyclopedia. https://encyclopedia.pub/entry/17459
Shnayder, Natalia. "Extracellular Matrix in Skin Wound Healing." Encyclopedia. Web. 22 December, 2021.
Extracellular Matrix in Skin Wound Healing
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This entry is adapted from the peer-reviewed paper 10.3390/jcm10245947

Impaired wound healing is one of the unsolved problems of modern medicine, affecting patients’ quality of life and causing serious economic losses. Impaired wound healing can manifest itself in the form of chronic skin wounds or hypertrophic scars. Research on the biology and physiology of skin wound healing disorders is actively continuing, but, unfortunately, a single understanding has not been developed. The attention of clinicians to the biological and physiological aspects of wound healing in the skin is necessary for the search for new and effective methods of prevention and treatment of its consequences. In addition, it is important to update knowledge about genetic and non-genetic factors predisposing to impaired wound healing in order to identify risk levels and develop personalized strategies for managing such patients. Wound healing is a very complex process involving several overlapping stages and involving many factors. Extracellular matrix has played a role in wound healing.

wound healing extracellular skin matrix violation of regeneration

1. Introduction

The ability of tissues to recover after damage is one of the fundamental properties of all organisms that underlies the maintenance of the body’s homeostasis [1]. The skin is the most important barrier of the body against the damaging effects of external factors; therefore, to maintain the integrity and homeostasis of the skin, there are complex mechanisms for self-defense and restoration of the integrity of the skin after damage. The skin is a more accessible organ than others for experiments in animals and humans; therefore, most of the fundamental research in the field of regenerative biology aimed at studying the mechanisms of repair is carried out on the skin, with the subsequent comparison of the results obtained with the mechanisms of regeneration in other epithelial–mesenchymal organs. All living organisms have mechanisms for tissue restoration after tissue damage, while in most vertebrates in the postembryonic period, healing occurs through scar formation [2]. Only fetal wounds can fully restore the integrity, biomechanics, and function of tissues, with the best regenerative wound healing. Wounds in adults are not capable of complete regeneration, and the wound surface is replaced by scar tissue. With the formation of scar tissue, fibrillar collagen accumulates, with a prolonged inflammatory process or impaired neovascularization. This scar tissue is less tear-resistant. At the same time, whereas the usual arrangement of fibrillar collagen fibers in the skin is in the form of a network, in scar tissue, fibrillar collagen accumulates in large quantities in the form of thick bundles running parallel to the length of the tissue.
Molecular and cellular causes of poor wound healing on the skin are being actively studied, but presently, the issue of prevention and effective treatment for wound healing remains open. Two questions are being actively discussed: “Why do some people experience pathological wound healing even with relatively minor trauma? How to prevent the formation of unfavorable scars on the skin?” [3].
Poor wound healing is a consequence of the disturbance of the action of factors in the process of tissue repair in response to damage and is the cause of lengthened processes of wound healing after surgery and skin damage, the formation of hypertrophic or atrophic scars, chronic trophic ulcers, and other pathological conditions [4]. Therefore, wounds that fail to proceed through the normal phases of wound healing are defined as chronic wounds [5]. The failure of cellular processes during the tissue repair process can be associated with the clinical state of the body (vascular diseases, diabetes mellitus, aging) and can also be caused by genetic variations in genes responsible for the components involved in the tissue repair process. In the latter case, research is focused on a genetic predisposition to pathological scarring of wounds [3], which refers to a multifactorial pathology [6][7]. Genetic predisposition is currently the least-studied predictor of impaired wound healing. There is clinical interest in the study of candidate genes in combination with the assessment of other factors, which will make it possible to assess the cumulative risk of impaired wound healing in patients undergoing surgical and nonsurgical treatments for skin lesions, including patients with atrophic scars. Cumulative assessment of the risk of damage to skin wounds is an important aspect of the development of a personalized algorithm for the management of such patients [8].

2. The Role of Extracellular Matrix in Skin Wound Healing

The dermis contains densely packed collagen fibers that provide the skin with tensile strength. However, when the skin is damaged, a number of processes are launched aimed at preventing the penetration of infection and restoring the integrity of the skin in the damaged area (wound) [9]. Closure of the wound edges occurs along Langer’s lines of tension, which, in turn, are histologically correlated with the orientation of collagen fibers. In the wound, collagen fibers intertwine and create a structural scaffold, allowing cell adhesion, chemotaxis, and migration. Excessive tension on collagen fibers in the early stages of wound healing can lead to the formation of hypertrophic scars. In contrast, a decrease in the tension of collagen fibers with laxity and age-related changes in the skin may be associated with a decrease in the production of collagen I and III at the stage of wound healing.
When a skin wound occurs, enzymes of the extracellular matrix are activated. The most important enzymes in the remodeling of the extracellular matrix are MMPs, disintegrin, and a metalloproteinase from the thrombospondin motif family (ADAMTS).
MMPs are a large family of zinc-dependent endopeptidases involved in the degradation of all major components of the extracellular matrix, including the basement membrane. Initially, MMPs are secreted as inactive zymogens with a propeptide domain that must be removed for MMP activation. MMP precursors include an amino pro-domain masking the catalytic zinc-binding motif [10].
Currently, at least 24 different MMPs are known, which can be soluble and membrane-bound. MMPs are classified according to their structural organization and substrate specificity into: collagenases; gelatinases; stromelysins; matrilisins; and membrane types of MMP. Under physiological conditions, MMP activity is tightly regulated. However, MMP activity increases with pathological processes. Inhibitors such as tissue MMP inhibitors (TIMPs) [11] inactivate MMPs of the extracellular matrix.
The following are involved in the regulation of cell phenotype, adhesion and migration: adamlysins-ADAMs (disintegrin and MMP); ADAMTS (adamlysins with thrombospondin motif) are extracellular matrix proteinases that are involved in the formation of cytokines, the release of growth factors, and degradation of components of the extracellular matrix. Heparanases and sulfatases degrade heparin sulfate, affecting its ability to bind multiple growth factors, altering signaling events [10].
MMPs first destroy collagen I, which restricts the migration of skin stromal cells. Then, MMPs act on elastin fibers, release peptides that act on wound healing, accelerate fibroblast proliferation, and increase collagen I and tropoelastin. These peptides are collectively called matrikines.
Matrikines are biologically active fragments obtained as a result of proteolytic cleavage of collagens, proteoglycans, elastin, and laminins. Thus, hyaluronan fragments regulate inflammation and wound healing. Further, with the interaction of integrin αvβ3 and elastin-binding protein, through protein kinase A, there is improvement in adhesion, migration, and proliferation of fibroblasts. Thus, SLRPs—decorin and lumican—are decoupled and removed from the adjacent matrix [12].
Fibrin, fibronectin, and vitronectin are key mediators of hemostasis and cell migration in wound healing. Fibrin is the first fibrous structure in wounds. It is formed from soluble blood plasma fibrinogen and forms a temporary clot matrix during wound healing. When fibroblasts migrate to the wound area, fibroblasts compress the fibrin matrix and use it as a surface for migration and tissue remodeling, replacing it with collagen and other extracellular matrix proteins [13].
During wound healing, fibronectin is involved in the organization and stabilization of the extracellular matrix. It is required for the deposition of collagen I and other extracellular matrix proteins, and it is also required to regulate the activity of lysyl oxidase, which is involved in strengthening collagen fibers. The plasma fraction of fibronectin is incorporated into the fibrin clot, providing a wound seal and a scaffold for leukocyte and endothelial cell migration. At the proliferation stage, fibronectin assembles into a complex three-dimensional structure on the cell surface, which provides tissue architecture and regulates cell adhesion, migration, proliferation, and apoptosis during skin wound healing. It is believed that the formation of further collagen networking depends on the initial fibronectin structure, through mechanisms involving integrins. Additionally, fibronectin is required for the neovascularization of a healing wound [13].
Stimulation of the proliferative activity of fibroblasts through TGF-β depends on the preliminary assembly of the fibronectin matrix. Fibronectin is commonly present in the acute phases of inflammation and wound remodeling. At low tissue tension, fibronectin binds collagen fibers. Then, a network of fibril collagens is formed, replacing fibronectin fibers and creating a high tension of the extracellular matrix [14].
Insoluble fibronectin bundles are formed from the soluble fraction in blood plasma. In the acute phase of wound healing, fibronectin binds to integrin αvβ3 (expressed by fibroblasts) and stimulates their migration into the wound. Additionally, fibronectin has a site for binding and stabilizing fibrin (a prerequisite for the migration of fibroblasts), and it also interacts with other cells and fibrils involved in wound healing in the skin.
Vitronectin is important for the early contraction of skin wounds. Thus, the creation of tension of collagen fibers in the wound area is provided by fibroblasts, which first attach to fibronectin, then to vitronectin, and only after that to collagen. Vitronectin affects fibroblast proliferation mediated by fibronectin. Vitronectin is a kind of modulator of the migrating and proliferating response of fibroblasts [15].
Another unique component that plays a role in the regeneration of skin wounds is tenascin-C. The expression of this protein in intact tissues is minimal. Expression increases with tissue damage (wound) [16]. Tenascin-C is a matrix and has many repeats of fibronectin-like integrin-binding domains and EGF-like repeats for binding to components of the extracellular matrix and signaling through the EGF receptor. Tenascin-C regulates cell adhesion and thus affects the functionality of the dermis during wound healing. Experimental data on axolotls have shown that low levels of fibronectin and high levels of tenascin-C promote optimal wound healing instead of pathological scarring.
In addition, the role of MMPs in the regulation of fibrotic response has been shown [17]. The greatest increases in osteopontin, tenascin C, TGF-β1, and TIMP1 occur in response to skin damage and an increase in MMP expression in the wound.
During wound healing, pro-migration dermatopontin and anti-migration decorin balance each other and mutually change their activity.
The presence of GAGs is required at the earliest stages of skin wound healing to facilitate the migration of fibroblasts through the CD44 receptors. At the same time, in the fetus (when there is no cicatricle wound healing), GAGs have a large molecule length. In studies comparing the regeneration process in a fetus and an adult wound, the importance of hyaluronic acid has been shown. Therefore, in the fetal wound, when the regeneration ends without scarring, there was a higher content of GAG and higher molecular weight of hyaluronic acid (which reduces angiogenesis and inflammation). The increased content of hyaluronic acid in the skin wound area persisted longer in the fetus than in adults (3 weeks versus 7 days) [18][19][20][21][22].
The secreted glycopeptide fibulin-5 binds and mediates the development of elastic fibers. Under normal conditions, it is inactive, and its expression is activated 14 days after the start of wound healing. Its overexpression induces the formation of granulation tissue and initiates remodeling of the extracellular matrix. At the same time, fibulin-5 does not affect the migration and proliferation of fibroblasts [16].
In addition, the extracellular matrix contains matrix-cell proteins. These proteins are secreted and interact in the extracellular matrix of autocrine and paracrine cells. They do not affect the mechanical structure of the extracellular matrix. Matrix-cellular proteins include osteopontin; osteonectin; thrombospondins −1 and −2; tenacin-C; fibulins; and proteins of the CCN family. These proteins act as signaling molecules that are dynamic over time. They can only be colonized in a skin wound, not present in healthy skin. During wound healing, these proteins act on fibroblasts. In turn, fibroblasts produce more of these proteins in the cutaneous wound. This process is a variant of autocrine regulation [16].
The fairly recently described osteopontin was first discovered in bone. In addition to participating in bone mineralization, osteopontin can also participate in the processes of fibrosis in the skin. It interacts with collagen and fibronectin and also contains several cell adhesion domains that interact with integrins and CD44. Osteopontin increases fibroblast migration and proliferation. It is required for myofibroblast differentiation in response to the TGF-β signal [23].
The glycoprotein most commonly found in bone is osteonectin (a secreted protein that is acidic and rich in cysteine). This protein is also associated with fibrosis in the skin and other tissues. It can increase gene expression and protein assembly, including collagen I.
Another matrix cell peptide, CCN2, is usually not present in the skin but appears when tissue is damaged (skin wounds). It increases the expression of collagen I and III by fibroblasts, tissue inhibitors of MMP, and basic fibroblast growth factor. At the same time, CCN2 does not affect the expression of proteoglycans. In addition, it stimulates the recruitment of mesenchymal stem cells to the wound site for their differentiation into fibroblasts. It is believed that the expression of CCN2 in the skin is associated with the formation of hypertrophic scars [24].
After tissue damage, fibroblasts produce various cytokines and growth factors; they differentiate into a highly contractile phenotype characterized by the expression of α-SMA—myofibroblasts, as described previously [25][26].

Genetic Aspects of the Role of Extracellular Matrix in Wound Healing

Currently, more than 100 genes are known that are responsible for the microenvironment involved in wound healing in the skin [27][28]. Studies in transgenic mice have shown the role of the earliest gene regulators, including the AP1 FOS, and JUN genes, as well as zinc finger transcription factors known as Krox, which are involved in the activation of transcription for several hundred other genes that provide cell proliferation [29]. Additionally, the epigenetic regulation is important, as we have already written about in a previous article [30].
Of great interest is the study of single nucleotide polymorphisms (SNPs) of genes responsible for the synthesis of collagen fibers, elastic fibers, and hyaluronic acid in different types of skin wound healing. Mutations in the genes responsible for the synthesis of skin collagen (for examples, collagen I, III, IV, V, VI, VII, XIV, XVI, and XVII types) lead to various skin pathologies, including abnormal wound healing [31].
In studies on mice with collagen III deficiency, spontaneous skin wounds and an uneven diameter of collagen fibrils were noted [32]. With a deficiency of COL3A1 expression in granulation tissue, a higher content of myofibroblasts was noted in experimental animals [33][34][35], and in humans, a mutation in the COL3A1 gene causes type IV Ehlers–Danlos syndrome, in which skin wounds heal with a large number of scars [18]. Mutations in the COL1A2 gene lead to an increased risk of hypertrophic scar formation after skin injury [36].
Thus, with Marfan syndrome, caused by mutations in the FBN1 gene encoding fibrillin-1, there is a decrease in the level of extracellular fibrillin-rich microfibrils, which usually act as a reservoir for TGF-β. As a result, TGF-β signaling is impaired during wound healing [37][38].
A study investigating the role of Lucilia sericata larvae in wound healing showed the highest expression of the COL1A2, COL4A1, CTSK, CCL7, ANGPt1, CD40lG, EGF, and ITGB5 genes in wound healing in an experiment [39]. Another study found a decrease in elastin content during the wound healing [40][41].
At present, studies of SNPs of these candidate genes in different types of healing of skin wounds continue.

3. Conclusions

Surgical treatment of skin wounds requires an interdisciplinary approach involving doctors of various specialties (dermatologists, plastic surgeons, microsurgeons, traumatologists, etc.). It is important to not only control the infection and ensure rapid closure of the skin wound, but also to be able to manage the healing process of skin wounds [42]. Various methods are proposed to control and improve the healing of wound skin lesions, including invasive (injections of platelet plasma, botulinum toxin type A, glucocorticosteroids) [43] and non-invasive (laser therapy, creams with growth factors and cytokines, silicones) approaches [44][45]. However, no single (“gold”) standard for managing skin wound healing has been developed [46].
In recent decades, bioengineering techniques have been developed that temporarily replace a skin defect [47], along with targeted drugs that block a specific signaling pathway for skin wound healing. Thus, blockading the TGFβ signaling pathway is considered a promising method [48][49][50].
Herein shows the significant role of the extracellular matrix of the skin in wound healing. Understanding the role of the extracellular matrix of the skin is important when we plan scar treatment. Before surgery, it is important to assess the risk of abnormal wound healing. Therefore, such risk assessment also includes consideration of violations of the functions of the extracellular matrix of the skin.
The search for biomarkers (predictors, risk factors) of pathological scarring of skin wounds continues. Along with external damaging factors and hereditary diseases, multifactorial pathology is of undoubted interest, including the carriage of risk alleles for SNP of candidate genes associated with abnormal wound healing. Therefore, additional fundamental and clinical studies are needed to study the mechanisms of pathological scarring and the possibilities of combination therapy to prevent pathological skin wound healing.

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