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Dermal and oral wound healing: Similarities and distinctions

Glim, J.E.

2014

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citation for published version (APA)Glim, J. E. (2014). Dermal and oral wound healing: Similarities and distinctions.

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17

CHAPTER 2

Detrimental dermal wound healing: What can we learn from the oral mucosa?

Judith E. Glim1,2, Marjolein van Egmond1,3, Frank B. Niessen2, Vincent Everts4, Robert H.J. Beelen1

1 Dept. of Molecular Cell Biology & Immunology 2 Dept. of Plastic and Reconstructive Surgery3 Dept. of Surgery, VU University Medical Center 4 Dept. of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), Amsterdam, The Netherlands

Wound Repair and Regeneration, 2013 Sep-Oct 21:648-660

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Chapter 2 | Dermal vs. oral wound healing

ABSTRACT

Wounds in adults are frequently accompanied by scar formation. This scar can become fibrotic due to an imbalance between extracellular matrix (ECM) synthesis and ECM degradation. Oral mucosal wounds, however, heal in an accelerated fashion, displaying minimal scar formation. The exact mechanisms of scarless oral healing are yet to be revealed. This review highlights possible mechanisms involved in the difference between scar-forming dermal vs. scarless oral mucosal wound healing. Differences were found in expression of ECM components, such as procollagen I and tenascin-C. Oral wounds contained fewer immune mediators, blood vessels, and profibrotic mediators but had more bone marrow-derived cells, a higher reepithelialization rate, and faster proliferation of fibroblasts compared with dermal wounds. These results form a basis for further research that should be focused on the relations among ECM, immune cells, growth factors, and fibroblast phenotypes, as understanding scarless oral mucosal healing may ultimately lead to novel therapeutic strategies to prevent fibrotic scars.

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Dermal vs. oral wound healing | Chapter 2

INTRODUCTION

Wound healing is a complex process involving a wide spectrum of cells and molecules. The complete process comprises several phases -hemostasis, inflammation, proliferation, and remodelling- that overlap in time and space. Dysregulation of wound healing can result in fibrotic disorders. Fibrotic or hypertrophic scars of the skin typically have a reddish appearance and rough texture and cause itching and pain.1 Additionally, these scars tend to protrude from the skin, making them aesthetically unpleasant. Fibrotic tissues are further characterized by excessive formation and accumulation of extracellular matrix (ECM) proteins, among them collagen, representing an increased collagen type III:I ratio. The collagen matrices are orientated parallel to the epidermal surface, in which thick collagen fibrils are present.2 Furthermore, myofibroblasts are abundantly observed in hypertrophic scars, representing another feature of fibrosis. Myofibroblasts are a unique type of fibroblasts that share characteristics of both fibroblasts and smooth muscle cells.3 They deposit high amounts of collagen and express α-smooth muscle actin (α-SMA), which is incorporated into actin stress fibers under conditions such as increased tension or after stimulation by transforming growth factor-β (TGF-β).4 A notable feature of myofibroblasts is their ability to generate increased contractile forces as a result of α-SMA incorporation. Because of this, α-SMA is used as a marker for myofibroblast identification. Interestingly, during the first and second trimesters of fetal gestation, wounds heal without scar formation. The immune system could be responsible for these differences between adult and fetal healing, as early fetal wounds heal without an inflammatory response.5 Apart from immune responses, other extrinsic factors could be involved in scarless fetal healing. For instance, amniotic fluid contains an abundance of growth and trophic factors that have been suggested to contribute to repair. Importantly, deficiency of the anti-inflammatory factor interleukin (IL)-10 in mice results in scar formation in fetal wounds, while overexpression promotes tissue regeneration in adult wounds-pieces of evidence that support the influence of the immune system.6, 7 Transplantation studies, however, have shown that scarless fetal healing is strictly attributable to the skin and not to the environment.8, 9 This notion was confirmed by a study that focused on skin ECM composition. Higher levels of chondroitin sulfate and fibronectin were present in fetal skin, while elastin was only present in adult skin.10 Furthermore, the fetal ECM is rich in collagen type III and hyaluronic acid (HA).11, 12 Early fetal skin, in

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comparison with postnatal skin, contains low amounts of the profibrotic growth factor TGF-β1 and high expression of the antifibrotic isoform TGF-β3.13 Fast reepithelialization and abundant fibroblasts have been observed in fetal wound healing, suggesting the speed of healing may play a role in scarless healing.14 Taken as a whole, it appears that ECM content, inflammation, growth factors, and fibroblasts may contribute to scarless fetal wound repair. Wounds of the oral mucosa tend to heal in an accelerated fashion and display no or minimal scar formation, comparable to fetal wounds.15 However, different oral regions have shown contradictory findings. Hakkinen et al.15 postulated that palatal and gingival wounds heal without scar, but the buccal mucosa displays minimal scarring. Contrary to this, other studies found palatal scarring in the form of a rigid scar following cleft palate repair, but did not observe scar hypertrophy.16 Tongue wounds heal quickly with few signs of inflammation. In this regard, the exact mechanisms of scarless oral healing are yet to be elucidated. Fibrosis and extensive scarring of many different organs is a serious problem, and there is a need for new insights to address this issue. In this review, we focus on factors involved in aberrant wound healing and discuss whether they are differently expressed in oral and dermal wound healing. As with fetal healing, we will concentrate on the composition of ECM, inflammatory mediators, growth factors, and fibroblast phenotypes. Finally, we will also discuss the role of mesenchymal stem cells during healing.

SKIN AND ORAL MUCOSA ARCHITECTURE

HistologyThe skin is composed of a keratinized epidermal layer, basal lamina, dermis, and subcutaneous tissue (Fig. 1).17 The epidermis functions as a barrier against harmful agents and prevents dehydration. Keratinocytes are the most abundant cells of the epidermis. They are tightly connected to each other by desmosomes and organized in a number of layers.18 In addition, small numbers of Langerhans cells, melanocytes, and Merkel cells reside in the epidermis. This upper layer of the skin can be subdivided into four layers: stratum corneum, stratum granulosum, stratum spinosum, and stratum basale. Keratinocytes start to migrate and differentiate from the stratum basale and eventually form the stratum corneum.

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The dermis plays a role in maintaining the turnover of protein content and provides support to the epidermis. This layer of the skin contains fibroblasts, mast cells, macrophages, blood vessels, and nerve endings.17 These structures are surrounded by ECM proteins, many of which are expressed as fibers. The fibers are mainly composed of collagen (type I and III) and lie perpendicular to the dermal surface. Fibroblasts are the main cells responsible for remodeling of ECM proteins. The subcutaneous tissue is the deepest part of the skin and consists largely of adipose tissue. Fibroblasts and mast cells are also found in this layer, together with blood vessels and nerves. This layer plays a role in thermoregulation, protection from injury, and provision of energy. The oral mucosa consists of an epithelial layer, a basal lamina, a lamina propria, and a submucosal layer that is attached to muscle or bone (Fig. 1).19, 20 The submucosa is not present in regions such as the hard palate and gingiva.21 In these areas, the lamina propria directly attaches to the periosteum of the bone. This is called the mucoperiosteum and provides a firm inelastic connection. Oral epithelia can be keratinized or nonkeratinized, depending on the location. Areas such as the palate and gingiva are exposed to mechanical forces and contain a keratinized epithelium that provides extra protection against abrasion.18 Oral parts that require flexibility in order to chew, swallow, or speak are covered by nonkeratinized epithelium. The tongue is parakeratinized: it consists of both keratinized and nonkeratinized epithelium.22 Though the keratinized oral mucosa and skin have comparable ECM composition, the nonkeratinized oral mucosa has a loose ECM structure that is more elastic. Elastin is only present in nonkeratinized epithelium.23 The presence or absence of elastin determines the expression of certain keratins. For instance, keratins 1 and 10 are exclusively present in keratinized epithelium, while keratins 4 and 13 are only present in nonkeratinized epithelium. Eradication or addition of elastin changes the keratin expression, indicating that keratin expression is mediated by the expression of elastin in the lamina propria.23 If we compare the oral mucosa with skin, it is apparent that the oral mucosal epithelium is thicker than skin epidermis (Fig. 1).24 All layers of the oral mucosa have functions comparable to those of skin layers, but the skin contains a variety of adnexa, e.g., sweat glands, sebaceous glands, and hair follicles, while the oral mucosa only features salivary glands.

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Figure 1: Schematic representation of skin and oral mucosa histology. The epidermis and oral epithelium mainly consist of keratinocytes and a few Langerhans cells. The oral epithelium contains, however, more cell layers than the epidermis and can be keratinized or nonkeratinized. Both dermis and lamina propria are separated by a basal lamina and include nerves, blood vessels, fibroblasts, mast cells, and macrophages, which are surrounded by extracellular matrix proteins. The subcutaneous layer and submucosa consist mainly of adipose tissue, but fibroblasts, blood vessels, and nerves are also present. The submucosa is not present at every part of the oral cavity. In these areas, the lamina propria is directly connected to bone structures.

KeratinocytesSeveral differences have been observed between dermal and oral keratinocytes (obtained from keratinized epithelium) in response to inflammatory stimuli. After treatment with tumor necrosis factor (TNF)-α, interferon (IFN)-γ, or IL-4, human oral keratinocytes produce higher levels of IL-6 compared with human dermal keratinocytes. In addition, a more rapid increase of IL-6 production is found in oral keratinocytes.25 IL-1β induces higher production of IL-6 and TNF-α by dermal than by oral (palate) human keratinocytes.26 TNF-α increases IL-8 production in both dermal and oral mouse keratinocytes, albeit to a greater degree in oral keratinocytes. IL-1α induces IL-8 production in oral but not dermal human keratinocytes.26 Oral tongue wounds in mice show complete reepithelialization

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within 24 hours postwounding, while dermal wound closure is only observed after 60 hours to 7 days.27,28 These data indicate that oral keratinocytes act faster and are more robust to inflammatory stimuli than dermal cells.

Blood vessels Endothelial progenitor cells (EPCs) derive from bone marrow and contribute to vasculogenesis in processes requiring neovascularization, such as wound healing. The CC-chemokine receptor CCR5 has been shown to be an important modulator for EPC recruitment to wounded areas.29 Additionally, EPCs are an important source of growth factors (e.g., vascular endothelial growth factor [VEGF] and TGF-β1), required for repair. In a mouse model it was shown that EPCs enhanced wound reepithelialization and neovascularization and, in addition, promoted macrophage recruitment to the wound.30 This indicates that EPCs may be a promising target in accelerating wound closure, although elevated numbers of blood vessels have also been correlated with hypertrophic scars.31, 32 When oral and dermal tissue are compared, similar numbers of blood vessels are found in both types of tissue.33 After red Duroc pigs and mice are wounded, the number of blood vessels increases in both oral and skin wounds, although significantly more vessels are found in the skin compared with the oral mucosa.33, 34 Another important factor for new vessel formation is VEGF, regarding which no differences have been found between undamaged dermal and undamaged oral tissue. After injury, however, mouse oral mucosal wounds express lower levels of VEGF than their dermal.34

Extracellular matrix The ECM, or connective tissue, provides structural support to the surrounding tissues, permits cellular adhesion, and serves as a barrier for fluids and macromolecules. Collagen is the most abundant ECM protein-up to this point,28 different isoforms have been discovered.35 Only collagens I, II, III, V, and XI can arrange themselves into fibrils, and this is mainly seen in areas subjected to tension or pressure forces.36 During wound healing of the dermis in mice, collagen fibers have a smaller diameter than in unwounded tissue. Interestingly, in both normal and wounded oral mucosa, the fibril diameter is similar.28 In pigs, the number of cells positive for procollagen type I is significantly increased in skin wounds compared with oral mucosal wounds.24

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The ECM proteins fibronectin splice variant extra domain A (FN ED-A), HA, and tenascin-C (TN-C) are highly expressed during both embryogenesis and wound healing. Differences have been found in the expression of these molecules during oral and dermal wound healing. FN ED-A has been suggested to play a role in the development of fibrosis, as FN ED-A knockout mice fail to develop fibrosis.37, 38 In addition, fibroblasts obtained from fibrotic lungs produce more FN ED-A than normal fibroblasts.38 FN ED-A shows prolonged presence in skin wounds of red Duroc pigs compared with oral palatal wounds.24 Basal levels of TN-C are elevated in the oral palatal mucosa in comparison with the skin. After wounding, TN-C persists longer in the oral palatal mucosa of both red Duroc pigs and humans.24 TN-C knockout mice display delayed wound healing when compared with wild-type mice.39 Together, these results indicate that increased and prolonged expression of TN-C may be necessary for accelerated wound healing. HA synthesis depends on the activity of hyaluronan synthase (HAS), of which three different isoforms (HAS-1, HAS-2, and HAS-3) have been found.40 HAS-1 and HAS-2 synthesize high-molecular weight (MW) HA, while low-MW HA is generated by HAS-3. Interestingly, it has been shown that MW variants of HA have different effects. Medium-MW HA (100-300 kDa) improves human keratinocyte migration, in contrast to low-(5-200 kDa) and high- (1000-1400 kDa) MW HA.41 This suggests that HA with the right MW might be used for therapeutic interventions. HAS-1 mRNA expression is absent in oral human fibroblasts but abundant in dermal fibroblasts, while for HAS-3 mRNA expression the converse is true.42 TGF-β1 induces HAS-1 expression in dermal but not in oral mucosal fibroblasts.43 HAS-2 is found in both populations, and stimulation with TGF-β1 increases its expression in dermal fibroblasts but decreases it in their oral counterparts. Another difference between human oral and dermal fibroblasts related to HA expression has been found: Migration-stimulating factor (MSF), which is a truncated form of fibronectin, is only produced by gingival and not by dermal fibroblasts.44 Furthermore, MSF stimulates the production of especially high-MW HA. This result, however, is in contrast with the finding that oral fibroblasts have increased expression of HAS-3, the synthase that produces low-MW HA. Finally, more HA is found in the rat palatal mucosa than in the skin or gingiva.45 The ECM is dynamic, with continuous remodeling taking place. Digestion of ECM is mediated by both cysteine proteinases and matrix metalloproteinases (MMPs), secreted by fibroblasts, endothelial cells, keratinocytes, macrophages,

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and many other cell types.46 The activity of MMPs is counteracted by tissue inhibitors of MMPs (TIMPs). An imbalance between MMP and TIMP activity has been implicated in fibrotic diseases. With respect to fetal wound healing, higher ratios of MMPs to TIMPs are found in early-gestational wounds compared with late-gestational wounds.47 Moreover, keratinocytes obtained from hypertrophic scars display increased production of TIMP-1 that may be responsible for the increased collagen deposition found in these scars.48 Furthermore, significantly higher levels of MMP-3 (stromelysin-1) are produced by human oral fibroblasts than by dermal ones, though TGF-β1 and TGF-β3 increase MMP-3 expression in both oral and dermal fibroblasts.49, 50 Initially, human oral buccal fibroblasts seem to produce more active MMP-2 than their dermal counterparts, but mRNA and proMMP-2 expression do not differ between these two cell populations.51 This effect is explained by enhanced TIMP-1 and -2 production by dermal fibroblasts, which may in turn lead to deactivation of MMP-2. Gene expression of human MMP-12, however, is higher in dermal than in gingival fibroblasts.52 exact roles of the different MMPs in wound healing have not yet been elucidated. However, it has been suggested that MMP-2 can accelerate cell migration, that MMP-3 is required for wound contraction, and that MMP-12 may be involved in angiogenesis.53 Generally, MMP expression in the oral mucosa tends to accelerate healing, while in the skin it increases angiogenesis, which is in line with other observations discussed throughout this review.

Saliva Saliva has been proven to be important for oral wound healing. Human subjects suffering from xerostomia, which is a perception of dry mouth mainly caused by reduction or absence of saliva, experience delayed healing of oral wounds.54 Removal of rat salivary glands even resulted in increased and prolonged expression of immune mediators, suggesting a relation between saliva and the immune system.55 The salivary antimicrobial peptide (AMP) histatin accelerates wound closure in both dermal and oral fibroblasts in vitro, indicating that histatin can be beneficial for both oral and dermal repair.56 Salivary leptin increases oral keratinocyte cell proliferation and secretion of epidermal growth factor and keratinocyte growth factor (KGF), thereby contributing to accelerated repair.57 Also, in the skin, leptin accelerated the repair process in a mouse model.58 Besides saliva, some AMPs (e.g. β-defensins-1, -2, and -3 and psoriasin) are present in the skin, although in smaller amounts than in the oral mucosa.59

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Although no huge differences between oral and dermal tissues have been found, the role of saliva and its components is noteworthy, as it appears to be beneficial for wound repair. Overall, skin and oral mucosa tend to differ on an architectural level. Keratinocyte reactions and ECM content are different in dermal and oral wound healing (Table 1). Furthermore, a favorable effect on oral healing has been attributed to salivary components. These environmental or anatomical differences may be important for whether scar-forming or scar-free wound healing will take place.

IMMUNE CELLS AND MEDIATORS

Mast cellsMast cells are bone marrow-derived immune cells that are mainly found in perivascular spaces of connective tissue within the skin and mucosa. Upon activation or tissue injury, these cells degranulate, thereby releasing agents such as histamine, proteases (e.g., chymase and tryptase), prostaglandins, leukotrienes, inflammatory mediators (e.g., IL-1 and TNF-α), and growth factors (e.g., TGF-β1, platelet-derived growth factor [PDGF]). Mast cells play a primary role in hypersensitivity reactions and throughout all phases of wound healing. It is suggested that mast cells contribute to fibrosis. When cells of the mast cell-line HMC-1 were co-cultured with dermal fibroblasts, the latter increased α-SMA expression.60

In hypertrophic scars, increased numbers of mast cells are found compared with normotrophic scars.61 When the mast cell stabilizer ketotifen was administered in red Duroc pigs, a reduction in wound contraction was observed.62 Wounds generated in mouse embryos of embryonic day 15 (E15) not only have reduced numbers of mast cells in comparison to wounds in E18 embryos, but these cells are also less mature and do not degranulate.5 Sixty days after wounding, Mak et al.33 found a reduced presence of mast cells in pig oral wounds as compared with their dermal counterparts. These studies indicate that mast cells could be players in the formation of fibrosis in the skin.

NeutrophilsAs indicated previously, neutrophils are some of the first immune cells present at the site of injury. Neutrophil attraction is mediated by a number of mediators such

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as IL-8, the collagen breakdown product N-acetyl-Pro-Gly-Pro, or H2O2 produced by damaged epithelium.63, 64 Neutrophils have been proven to play a role in the aggravation of scar formation. The effect of oral tolerance on inflammatory cell influx after wounding was investigated by Costa et al.65 Mice were made orally tolerant for the antigen ovalbumin (OVA). Later, the mice were injected with OVA and a thoracic incision was made. The number of neutrophils, as well as numbers of mast cells and lymphocytes, was reduced around the lesion area of OVA-tolerant.65 Additionally, these tolerant mice showed a diminished scar area and normal ECM deposition, pointing to the role of immune cells in scar formation. A mouse study revealed that oral mucosal tongue wounds contained fewer neutrophils than dermal wounds.27 This could indicate that neutrophils are responsible for reduced scar formation, as wounds of both orally tolerant mice and the oral mucosa heal with reduced scar formation and have a diminished neutrophil influx.

MacrophagesAnother type of immune cell that has been thoroughly studied in the context of wound healing is the macrophage. These cells consist of a heterogeneous population and can roughly be classified into more classically (M1) or alternatively (M2) activated phenotypes.66 Following tissue injury, M1 macrophages are the first type of macrophages to respond, producing high amounts of pro-inflammatory cytokines and mediating antimicrobial activity. This response, however, must be controlled to prevent excessive tissue damage. For tissue restoration, M2 macrophages are important.67 M2 macrophages have been shown to express the ECM molecules fibronectin and TN-C.68, 69 This suggests that M2 macrophages are involved in ECM deposition and tissue remodeling in the late phase of tissue repair. In co-culture experiments, M2 macrophages induce fibroblast proliferation and collagen production.70 M1 macrophages, on the other hand, reduce fibroblast collagen production. In addition, levels of the profibrotic factors PDGF-AA, -BB and -CC are up-regulated in M2 macrophages, while levels of TNF-α and the collagen degradation protein MMP-7 are elevated in M1 macrophages.70, 71 Several studies have investigated the role of macrophages during wound healing using depletion models. Macrophage depletion leads to the following events: massive neutrophil influx (mouse),72 increased levels of macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 (MCP-1), cyclooxygenase-2

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and IL-1β expression, delayed reepithelialization and vascularization, reduced granulation tissue formation, decreased collagen deposition, and finally, prevention of myofibroblast differentiation and appropriate wound contraction.72, 73 Furthermore, it has been shown that macrophage depletion during the early stages of repair in particular has detrimental effects on healing.74

Oral wounds contained reduced numbers of macrophages compared with dermal counterparts in a mouse and pig wound model.27, 33 Macrophages, however, seem to be important for proper repair, as described above. Perhaps a small number of these cells is enough for fast and accurate healing, while more macrophages provoke scarring. In addition, the macrophage phenotype (M1 or M2) could be of importance, but to our knowledge, no studies have investigated this in dermal and oral wounds.

T- cellsAbout 5 days after wounding, T-cells migrate into the injured tissue, and their numbers peak on day 7.75 The exact role for T-cells in wound healing is not yet understood, although increased numbers of CD4+ T-cells have been found in hypertrophic scar tissue of burn patients.76 These cells have the capacity to increase collagen synthesis and induce α-SMA expression by dermal fibroblasts. CD4+ T-cells of these burn patients produced more of the profibrotic growth factor TGF-β than cells of healthy individuals. In addition to peripheral T-cells, resident T-cells play a role in tissue remodelling. Resident T-cells are found in dermis and epidermis and produce growth factors, such as insulin-like growth factor-1 (IGF-1), to support keratinocyte survival and proliferation.77 Two distinct populations have been found, γδ and αβ T-cells, whose functions in wound healing are not completely defined. In response to damaged keratinocytes, γδ T-cells produce cytokines and proliferate. γδ T-cells are important mediators for wound healing, as depletion induces a significant delay in wound closure.78 KGF-1 and -2 are produced by activated γδ T-cells, and absence of these growth factors may be responsible for a diminished reepithelialization. One study found a significant decrease of T-cells in oral mouse wounds as compared with their dermal counterparts.27

Cytokines, chemokines, and growth factorsFibroblasts obtained from hypertrophic scars produce more MCP-1, IL-6, IL-8, and prostaglandin E2 (PGE2) than normal skin fibroblasts, indicating that increased

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inflammatory responses might contribute to hypertrophic scar formation.79 Correspondingly, IL-6 or IL-1 receptor antagonist deficiency in mice causes a delay in wound healing with respect to leukocyte infiltration, angiogenesis, and collagen accumulation.80, 81 Mice deficient for IL-1 receptor showed a diminished healing rate in oral, but not in dermal, wounds compared with wild-type mice.82 This effect was caused by limited clearance of infection in these deficient mice, as administration of antibiotics restored the normal healing rate.82, 83 In murine tongue wounds, IL-6 and KC (mouse homolog of human IL-8) are up-regulated for a short time (up to 24 hours), while dermal wounds display prolonged expression (72 hours) of these cytokines.27 IL-23, IL-24, and IFN-α and -β are significantly expressed in dermal but not in tongue wounds in mice.84 As seen with keratinocytes, inflammation seems to be reduced or less prolonged in oral wounds as compared with dermal ones. Of the chemokines, CC-chemokine ligand (CCL)5, CCL12, and CXC-chemokine ligand (CXCL)10 appear in mouse tongue wounds only, while CCL3, CCL20, CXCL3, CXCL7, and CXCL13 are only present in dermal wounds.84 Interestingly, if we look at the function of these chemokines, oral mucosal wounds express chemokines chemotactic for monocytes, while dermal wounds mainly express neutrophil-attracting chemokines. The growth factors PDGF-CC and connective tissue growth factor (CTGF) have been associated with fibrotic diseases. PDGF-CC overexpression caused renal fibrosis in mice, which was diminished by anti-PDGF-CC monoclonal antibody treatment.85 CTGF mRNA expression is up-regulated in hypertrophic scars, and mice deficient for CTGF failed to develop fibrosis when exposed to the fibrotic agent bleomycin.86, 87 Although these data strongly suggest that PDGF-CC and CTGF play a role in detrimental scar formation, the difference in expression between oral and dermal wound repair remains unknown. Insulin-like growth factor-2 (IGF-2) is preferentially expressed by gingival fibroblasts as compared with dermal counterparts.52 This growth factor is highly active in fetal development but considerably less active during adulthood. IGF-2 plays a key role in cell proliferation and differentiation, phenomena that occur in abundance during oral repair. Initially, IGF-2 was considered a promising candidate to improve wound repair, but it is also involved in fibrotic conditions and malignancies.88, 89

Transforming growth factor-βThe most intensively studied growth factor in relation to wound healing is TGF-β. This multifunctional cytokine plays a central role in tissue repair. Initially after

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wounding, TGF-β is secreted by platelets, and serves as a chemoattractant for parenchymal cells and leukocytes, which in turn enhance production of TGF-β. TGF-β stimulates the production of ECM by fibroblasts and inhibits ECM degradation. This mechanism leads to restoration of tissue architecture in normal wound repair, although overproduction may lead to fibrosis. In mammals, three different isoforms are found (TGF-β1, 2, and 3), and these are secreted in a latent form.90 Latent TGF-β resides in the matrix and becomes activated via proteolytic cleavage by, for example, proteases (plasmin, thrombin, MMPs), thrombospondin-1, integrins, or reactive oxygen species or by alterations and disruption of the ECM.91 TGF-β1 has a more profibrotic role, as increased expression is found in fibrotic diseases such as hypertrophic scars.92, 93 A mouse study revealed that elevated TGF-β1 production is associated with IFN-γ deficiency.94 This association was established in hypertrophic scar patients who had undetectable levels of IFN-γ.93 In addition, IFN-γ reduces proliferation and collagen synthesis in hypertrophic scar-derived fibroblasts.95 Finally, IFN-γ treatment results in more flattened hypertrophic scars.96

TGF-β1 mRNA and protein levels are significantly reduced in oral wounds compared with dermal wounds.27, 28, 33, 97 Early gingival wounds have higher expression of the antifibrotic isoform TGF-β3, and this growth factor persists for a longer period in them as compared with their dermal counterparts.98 Interestingly, TGF-β1 reduces proliferation in oral fibroblasts but increases proliferation in dermal fibroblasts.99

Overall, it appears that the majority of immune mediators are reduced in oral, compared with dermal wound healing (Table 1). These data are in line with results found in early fetal wounds, where neutrophils, macrophages and T-cells are absent.100 In late fetal wounds, immune cells are present, and these wounds heal in a more scar-forming fashion. These results indicate that immune responses play a crucial role in the outcome of scar-free or scar-forming repair.

FIBROBLASTS

Differences between oral and dermal wound healing can also be attributed to fibroblasts. Fibroblasts play a beneficial role in the deposition and remodeling of the ECM. Upon injury, fibroblasts differentiate into myofibroblasts, mainly via the

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activation of TGF-β, and produce abundant ECM. Furthermore, myofibroblasts express SMA filaments in order to facilitate wound strength. A number of studies have investigated possible differences between the two fibroblast populations. Schrementi et al.28 described an activated phenotype in dermal fibroblasts extracted from mouse wounds, based on the presence of an enlarged nuclear membrane, expansion of cytoplasm, and abundance of rough endoplasmic reticulum.28 Oral (tongue) fibroblasts, however, were found to be less active or even inactive. The proliferation rate was higher in oral, compared with dermal, fibroblasts.101

Human buccal mucosa fibroblasts produce increased amounts of the mitogens KGF and hepatocyte growth factor (HGF) compared with dermal fibroblasts, which may explain why oral wounds heal in an accelerated fashion.50, 102-104 Interestingly, TGF-β1 and 3 inhibit HGF and KGF production in both fibroblast types, thereby contributing to a diminished reepithelialization and finally delayed wound healing.50 Surprisingly, wound healing processes in KGF-deficient mice complete in a normal fashion.105 One explanation might be that fibroblast growth factor-10, another ligand for the KGF receptor, compensates for the lack of KGF, because blocking the KGF receptor does lead to a diminished reepithelialization.105

The growth factor PDGF-CC has been implicated in fibrosis in mice. Like TGF-β1, PDGF-CC stimulates fibroblasts to differentiate into myofibroblasts. Our group identified PDGF-CC production by M2 macrophages, although we did not find differences upon PDGF-CC treatment between human gingiva and dermal fibroblasts with respect to α-SMA expression.71

Contradictory results have been achieved regarding myofibroblast differentiation. Oral fibroblasts have been shown to express higher basal levels of α-SMA-positive myofibroblasts compared with dermal cells,33, 106 although the opposite has been shown as well.49, 50 Even up to 60 days after wounding, more myofibroblasts are found in oral mucosa wounds than in skin wounds.33 Interestingly, upon TGF-β1 stimulation, oral fibroblasts express less α-SMA than dermal fibroblasts, suggesting that oral fibroblasts are less responsive to TGF-β1.43, 106 Related to α-SMA expression is the observation that oral fibroblasts have a stronger contraction ability than dermal fibroblasts.50, 51, 106 The mast cell stabilizer ketotifen reduced the number of myofibroblasts in a pig wound model, indicating that inhibition of mast cell substances such as TGF-β and PDGFs reduces myofibroblast differentiation.62

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It is clear that dermal and oral (myo)fibroblasts differ in phenotype, as variations in responses have been found. This phenotypic difference could be crucial for the development of scar-forming or scarless healing, although the exact responsible factors are yet to be revealed.

MESENCHYMAL STEM CELLS

Mesenchymal stem cells (MSCs) were initially identified in the bone marrow, but appear to originate from many other tissues as well. Human MSCs are of nonhematopoietic lineage and are characterized by (1) adherent properties to plastic culture plates; (2) expression of the surface markers CD73, CD90, and CD105, but the absence of CD34, CD45, human leukocyte antigen-DR (HLA-DR), CD14 or CD11b, CD79α, and CD19; and (3) the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro.107 Furthermore, MSCs can differentiate into endothelial cells in vitro via VEGF stimulation.108 Other than these generalized markers and characteristics, there are no definitive markers for MSCs. In the skin, MSCs reside in the epidermis, hair follicles, and dermis, while in the oral mucosa these cells are located in exfoliated deciduous teeth, periodontal ligament, and the lamina propria.109, 110 Due to their self-renewing capacities, MSCs are believed to be good candidates for the improvement of wound healing. As reviewed by Hocking and Gibran111 MSC-based therapies in mice, rats, and humans mediate MSC differentiation, toward keratinocytes or toward endothelial cells. As a consequence, MSCs accelerate epithelialization but also increase angiogenesis and granulation tissue formation in dermal wounds. Interestingly, MSC injection reduced lung fibrosis in bleomycin-treated mice. Moreover, both collagen concentration and inflammation were reduced upon MSC treatment.112 Both bone marrow-derived MSCs (BMSCs) and gingiva-derived MSCs (GMSCs) are immunomodulatory and possess anti-inflammatory functions.113 Human GMSCs induce M2 macrophage polarization, enhance dermal wound healing in mice by rapid reepithelialization, and increase angiogenesis.114 This M2 induction might be mediated by PGE2, produced by MSCs, as PGE2 has been shown to elicit an M2 phenotype in macrophages.115 A few benefits of the use of GMSCs over BMSCs have been demonstrated. GMSCs display a higher proliferation rate than BMSCs and are easier to isolate. Small gingiva biopsies generate large numbers of MSCs, while only a small proportion of bone marrow contains MSCs.116 Furthermore, GMSCs are not

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↑, increased in oral tissue/wounds compared with dermal; ↓, decreased in oral tissue/wounds compared with dermal; =, equal between oral and dermal tissue/wounds.For definitions of acronyms, please see Abbreviations list.

Table 1: Differences between oral and dermal wounds.

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dependent on growth factors for expansion in culture and, interestingly, do not express HLA-DR, so they might be suitable for allogenous.116

BMSCs aside, Verstappen et al.117 investigated the role of the total bone marrow-derived cell (BMDC) population in wound healing. Interestingly, rat palatal mucosal wounds had a higher influx of BMDCs than skin wounds. This cell influx might also be correlated with the accelerated repair found in oral mucosal wounds.

Finally, mesenchymal stem cells appear to be beneficial for wound healing. Studies have investigated differences between bone marrow- and gingiva-derived MSCs. However, it would be more interesting to examine differences between skin- and oral-derived MSCs, which should be a topic of future research. To our knowledge, the presence of MSCs in dermal and oral mucosal wounds, as compared with each other, has not been investigated.

CONCLUSIONS AND PERSPECTIVES

This review highlights the possible mechanisms involved in the difference between scar-forming dermal and scarless oral wound healing. With regard to tissue architecture, several differences in expression of matrix proteins (e.g., FN ED-A and TN-C) have been found between dermal and oral healing. With the exception of TN-C and HA, differences in ECM composition in nonwounded tissue have not yet been studied, although this could be important for the difference between scar-free and scar-forming healing. This point should be further investigated, as it has already been shown that the ECM of fetal skin, which heals similarly to oral mucosa in a scar-free manner, differs from that of adult skin.10 The fetal-adult ECM difference could well be applicable in the oral-dermal situation. Next, inflammatory mediators have been proven to be important in the comparison between oral and dermal healing. Nearly all studied immune cells show a reduced presence in oral mucosal wounds compared with dermal wounds. Reduction of immune cells in the oral mucosa may be elicited by oral tolerance to, for example, food antigens. With respect to macrophages, M2 macrophages are important for wound healing but, at the same time, show profibrotic properties. As there is a lack of studies comparing the presence of M1 and M2 macrophages in oral and dermal wounds, it will be important for future work to focus on these cells. The formation of fibrosis has been attributed to growth factors such as PDGF-

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CC or CTGF, but their role in oral wound healing has not been examined. IGF-2 expression is elevated in gingival fibroblasts, although the consequences of this in terms of healing remain thus far unknown. A lot of attention has been paid to TGF-β, as oral fibroblasts show reduced proliferative response to the isoform TGF-β1. TGF-β3 expression, however, is increased in oral wounds. Furthermore, while oral fibroblasts show reduced proliferation, dermal fibroblasts exhibit increased proliferation upon TGF-β1 treatment, indicating that these two populations utilize different pathway mechanisms. With respect to MSCs, gingiva-derived MSCs have been shown to be more beneficial in wound healing than bone marrow-derived MSCs. Unfortunately, no studies have yet compared the presence of MSCs in oral and dermal wounds, but the field of MSCs and wound healing shows great promise for further research, as it has been shown that MSCs are beneficial for proper wound healing. Total populations of BMDCs, however, have been revealed to be higher in oral wounds than in their dermal counterparts. Finally, Figure 2 provides a schematic overview illustrating the many differences between oral and dermal wound healing found in this review. It clarifies that fewer profibrotic mediators are present in oral mucosal wounds. Furthermore, oral wounds contain a smaller amount of immune mediators and fewer blood vessels, but they have more BMDCs, a higher reepithelialization rate, and faster proliferation of fibroblasts than dermal wounds. Saliva could partially be responsible for the reduced immune reaction found in oral mucosal wounds. Taken as a whole, it seems that the complete process of repair is more rapid in oral than in dermal wounds. Though this review does not offer a straightforward answer to the problem of scarless oral healing, we have made clear that an abundance of knowledge has been gathered. Further research concerning expression of and relations between ECM, immune cells, growth factors, and fibroblast phenotypes is needed to gain a better understanding of the differences in mechanism between scar-forming dermal and scarless oral mucosal wound healing. This knowledge could then be used for therapeutic strategies to diminish or prevent fibrotic diseases such as hypertrophic scar formation.

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Figure 2: Schematic summary of the review at a glance. Reepithelialization of the wounded area is achieved more quickly by oral than dermal keratinocytes. Of the extracellular matrix components, procollagen-1 (PC-1)and FN ED-A remain up-regulated for longer in dermal wounds, while TN-C persists longer in oral wounds (presence indicated with small or large icons). Mast cells, neutrophils, macrophages, and T-cells are reduced in oral wounds in comparison with dermal wounds. IL-6 and IL-8 show prolonged expression in dermal wounds but were only briefly expressed in oral wounds. The cytokines IL-23, IL-24, IFN-α, and IFN-β and the chemokines CCL3, CCL20, CXCL3, CXCL7, and CXCL13 are absent and TGF-β1 is diminished in oral wounds, indicating a reduced inflammatory response in the oral mucosal wound. An important feature of the oral mucosa is that it contains saliva, which may be responsible for the reduced inflammatory response. CCL5, CCL12, and CXCL10 were present and TGF-β3 is increased in oral wounds. Furthermore, fewer blood vessels and less VEGF production are observed in oral wounds. Oral fibroblasts display an increased proliferation rate. Finally, a higher influx of BMDCs and more myofibroblasts are present in oral wounds. The abundance of mediators found in the two types of wound is depicted by the number of icons throughout the figure. See Abbreviations for definitions of acronyms.

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