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Integrin αvβ6 is an epithelial-specific receptor that binds and activates latent transforming growth factor-β1 (TGF-β1). TGF-β1 has been implicated as an endogenous inducer of hair follicle (HF) regression during hair cycling. We hypothesized that αvβ6 integrin–mediated TGF-β1 signaling regulates hair regeneration and HF involution. In wild-type (WT) mice, the expression of integrin αvβ6 was strongly upregulated in the outer root sheath (ORS) during early hair regeneration, and was specifically enhanced in the HF bulge region. Expression gradually decreased in late anagen and remained restricted to the bulge region in the catagen and telogen stage HFs. The first spontaneous hair cycle was not altered in β6 integrin knockout (β6−/−) mice. However, after depilation, β6−/− mice exhibited retarded HF regression compared with WT controls. β6−/− follicles contained significantly higher numbers of proliferating Ki67-positive keratinocytes than WT follicles at an identical cycle stage. The β6−/− follicles also demonstrated significantly reduced levels of TGF-β1 expression and Smad2 phosphorylation during early anagen and anagen–catagen transition. Our study indicates that αvβ6 integrin has an important inhibitory role in keratinocyte proliferation in both HFs and interfollicular epidermis. Thus, downregulated TGF-β1 signaling in β6−/− mice may affect bulge niche stem cell behavior.

Integrin αv[beta]6 is an epithelial-specific receptor that binds and activates latent transforming growth factor-[beta]1 (TGF-[beta]1). TGF-[beta]1 has been implicated as an endogenous inducer of hair follicle (HF) regression during hair cycling. We hypothesized that αv[beta]6 integrin-mediated TGF-[beta]1 signaling regulates hair regeneration and HF involution. In wild-type (WT) mice, the expression of integrin αv[beta]6 was strongly upregulated in the outer root sheath (ORS) during early hair regeneration, and was specifically enhanced in the HF bulge region. Expression gradually decreased in late anagen and remained restricted to the bulge region in the catagen and telogen stage HFs. The first spontaneous hair cycle was not altered in [beta]6 integrin knockout ([beta]6(-/-)) mice. However, after depilation, [beta]6(-/-) mice exhibited retarded HF regression compared with WT controls. [beta]6(-/-) follicles contained significantly higher numbers of proliferating Ki67-positive keratinocytes than WT follicles at an identical cycle stage. The [beta]6(-/-) follicles also demonstrated significantly reduced levels of TGF-[beta]1 expression and Smad2 phosphorylation during early anagen and anagen-catagen transition. Our study indicates that αv[beta]6 integrin has an important inhibitory role in keratinocyte proliferation in both HFs and interfollicular epidermis. Thus, downregulated TGF-[beta]1 signaling in [beta]6(-/-) mice may affect bulge niche stem cell behavior.

Many preparations of CHX or fluoride are available for the prevention of gingivitis and caries (Table 2). Luoma et al.(f.16) states that \"clinical observations indicate single chemical agents used in prevention of dental diseases exert their action merely or predominately against either caries or gingivitis.\" McDermid et al.(f.18) has proposed that a combination of an anticaries and antiplaque agent may be useful and provide an additive protective effect if each agent acts at a different site. A potentially useful combination of CHX in any oral hygiene product with the addition of fluoride could be beneficial in reducing caries increments.(f.29) Since there can be an inhibitory effect on acid production and plaque formation by CHX, it may reduce the cariogenic challenge enough for fluoride to act more effectively.(f.27) There is evidence that, when used together for caries prevention, CHX and Fl provide additive benefits and together may prove valuable in the prevention of oral diseases.(f.12) A number of studies have been conducted on the effects of combining CHX and fluoride in the same vehicle and their interactions with one another (Table 2).(f.5,6,12-17,21,22) In spite of their opposite charges they have been shown to be successfully incorporated into the same vehicle without affecting their individual activity.(f.5,6,12-17,21,27,28) It appears that there is more damage to the outer structures of S. mutans by the combination of CHX and fluoride than by each agent alone.(f.20) It has been speculated that a combination of CHX and fluoride could exhibit a decrease in caries production and gingival inflammation.(f.6) There is clinical evidence that this is possible.(f.16) It has been shown that, when used together topically, sodium fluoride (NaF) and CHX in the same vehicle do not decrease the presence of free ionized fluoride or its protective action on enamel,(f.6,16) nor reduce the availability of CHX below therapeutic levels.(f.6,19) Chlorhexidine, a strong cationic compound, has the ability to form low-solubility salts with anions such as sulphate, phosphate and chloride(f.24,25) which can make it a difficult agent to incorporate into dental products without losing its antiseptic properties through interactions with other ingredients.(f.2) A fluoride used commonly in toothpaste, monofluorophosphate (MFP), was studied for its possible compatibility in formulations with CHX.(f.2) Results from this study showed that when clinically relevant concentrations of 0.2% CHX and 8.0% MFP were used, a visible precipitate formed in all samples.(f.2) This eliminated a large portion of the free CHX, leading the authors to conclude that MFP and CHX are not compatible.(f.2) In a study by Dolles et al.(f.5) it was found that when 2.0% CHX and 0.1% NaF were used together in a toothpaste, the NaF could be fully recovered, leading to the conclusion that ingredients other than the NaF were interacting and binding with the CHX. Sodium lauryl sulphate, a detergent commonly used in dentifrices, was studied for its compatibility with CHX and also found to react with and render CHX ineffective.(f.1) The time intervals of 3 to 120 minutes between use of CHX and sodium lauryl sulphate also showed that use of the two agents at a 3 minute interval did not decrease the plaque index and in fact the two agents need to be used at least 30 minutes apart or preferably greater than 120 minutes apart.(f.1) It is apparent that ingredients in toothpaste which are anionic such as sodium lauryl sulphate and MFP can have adverse affects on CHX both before and after its use. This may be due to ionic interactions(f.21) but to date no such interactions have been found with NaF and CHX.(f.12)

Standard cell cultures are performed in aqueous media with a low macromolecule concentration compared to tissue microenvironment. In macromolecular crowding (MMC) experiments, synthetic polymeric crowders are added into cell culture media to better mimic macromolecule concentrations found in vivo. However, their effect on cultured cells is incompletely understood and appears context-dependent. Here we show using human gingival fibroblasts, a cell type associated with fast and scarless wound healing, that MMC (standard medium supplemented with Ficoll 70/400) potently modulates fibroblast phenotype and extracellular matrix (ECM) composition compared to standard culture media (nMMC) over time. MMC significantly reduced cell numbers, but increased accumulation of collagen I, cellular fibronectin, and tenascin C, while suppressing level of SPARC (Secreted Protein Acidic and Cysteine Rich). Out of the 75 wound healing and ECM related genes studied, MMC significantly modulated expression of 25 genes compared to nMMC condition. MMC also suppressed myofibroblast markers and promoted deposition of basement membrane molecules collagen IV, laminin 1, and expression of LAMB3 (Laminin Subunit Beta 3) gene. In cell-derived matrices produced by a novel decellularization protocol, the altered molecular composition of MMC matrices was replicated. Thus, MMC may improve cell culture models for research and provide novel approaches for regenerative therapy.

Soft tissue calcification occurs in many parts of the body, including the gingival tissue. Epithelial cell-derived MVs can control many functions in fibroblasts but their role in regulating mineralization has not been explored. We hypothesized that microvesicles (MVs) derived from gingival epithelial cells could regulate calcification of gingival fibroblast cultures in osteogenic environment. Human gingival fibroblasts (HGFs) were cultured in osteogenic differentiation medium with or without human gingival epithelial cell-derived MV stimulation. Mineralization of the cultures, localization of the MVs and mineral deposits in the HGF cultures were assessed. Gene expression changes associated with MV exposure were analyzed using gene expression profiling and real-time qPCR. Within a week of exposure, epithelial MVs stimulated robust mineralization of HGF cultures that was further enhanced by four weeks. The MVs taken up by the HGF's did not calcify themselves but induced intracellular accumulation of minerals. HGF gene expression profiling after short exposure to MVs demonstrated relative dominance of inflammation-related genes that showed increases in gene expression. In later cultures, OSX , BSP and MMPs were significantly upregulated by the MVs. These results suggest for the first time that epithelial cells maybe associated with the ectopic mineralization process often observed in the soft tissues.

Connexins (C×s) are a family of transmembrane proteins that form hemichannels and gap junctions (GJs) on the cell membranes, and transfer small signaling molecules between the cytoplasm and extracellular space and between connecting cells, respectively. Among C×s, suppressing C×43 expression or function promotes skin wound closure and granulation tissue formation, and may alleviate scarring, but the mechanisms are not well understood. Oral mucosal gingiva is characterized by faster wound closure and scarless wound healing outcome as compared to skin wounds. Therefore, we hypothesized that C×43 function is down regulated during human gingival wound healing, which in fibroblasts promotes expression of genes conducive for fast and scarless wound healing. Cultured gingival fibroblasts expressed C×43 as their major connexin. Immunostaining of unwounded human gingiva showed that C×43 was abundantly present in the epithelium, and in connective tissue formed large C×43 plaques in fibroblasts. At the early stages of wound healing, C×43 was strongly down regulated in wound epithelial cells and fibroblasts, returning to the level of normal tissue by day 60 post-wounding. Blocking of C×43 function by C×43 mimetic peptide Gap27 suppressed GJ-mediated dye transfer, promoted migration, and caused significant changes in the expression of wound healing-associated genes in gingival fibroblasts. In particular, out of 54 genes analyzed, several MMPs and TGF-β1, involved in regulation of inflammation and extracellular matrix (ECM) turnover, and VEGF-A, involved in angiogenesis, were significantly upregulated while pro-fibrotic ECM molecules, including Collagen type I, and cell contractility-related molecules were significantly down regulated. These responses involved MAPK, GSK3α/β and TGF-β signaling pathways, and AP1 and SP1 transcription factors. Thus, suppressed function of C×43 in fibroblasts promotes their migration, and regulates expression of wound healing-associated genes via AP1, SP1, MAPK, GSK3α/β and TGF-β signaling pathways, and may promote fast and scarless wound healing in human gingiva.

Platelet-Rich Fibrin (PRF) is a second-generation autologous blood concentrate widely applied in regenerative medicine and dentistry for its wound-healing potential. Its clinical applications span dermatology, plastic surgery, periodontology, implantology, and oral maxillofacial surgery, with growing evidence supporting its effectiveness in tissue regeneration. Fibroblasts, as central regulators of extracellular matrix synthesis and remodeling, angiogenesis, and inflammation, are important targets of PRF's regenerative effects. This review summarizes the recent evidence of role of PRF in regulation of fibroblast functions important for wound healing and inflammation. It highlights PRF as a biologically active scaffold that accelerates soft tissue repair, primarily through modulation of fibroblasts, positioning it as a promising adjunct in regenerative therapies.

Integrin‐mediated cell–ECM (extracellular matrix) adhesion is a fundamental process that controls cell behaviour. For correct cell–ECM adhesion, both the ligand‐binding affinity and the spatial organization of integrins must be precisely controlled; how integrins are regulated, however, is not completely understood. Kindlins constitute a family of evolutionarily conserved cytoplasmic components of cell–ECM adhesions that bind to β‐integrin cytoplasmic tails directly and cooperate with talin in integrin activation. In addition, kindlins interact with many components of cell–ECM adhesions—such as migfilin and integrin‐linked kinase—to promote cytoskeletal reorganization. Loss of kindlins causes severe defects in integrin signalling, cell–ECM adhesion and cytoskeletal organization, resulting in early embryonic lethality (kindlin‐2), postnatal lethality (kindlin‐3) and Kindler syndrome (kindlin‐1). It is therefore clear that kindlins, together with several other integrin‐proximal proteins, are essential for integrin signalling and cell–ECM adhesion regulation.

Oral Wound Healing: Cell Biology and Clinical Management brings experts from around the world together to provide an authoritative reference on the processes, principles and clinical management of wound healing in the oral mucosa. Promoting a thorough understanding of current research on the topic, this new resource draws together thinking on the basic biological processes of wound healing in the oral environment, as well as providing more detailed information and discussion on processes such as inflammation, reepithelialization and angiogenesis. Beyond this, the book goes on to examine topics pertinent to the effective clinical management of oral wound healing, bringing together chapters on large dento-facial defects, dental implants, periodontal regeneration, and pulp healing.An essential synthesis of current research and clinical applications, Oral Wound Healing will be an indispensable resource for dental specialists, oral and maxillofacial surgeons as well as researchers in oral medicine and biology.

Scar formation following skin injury can be a major psychosocial and physiological problem. However, the mechanisms of scar formation are still not completely understood. Previous studies have shown that wound healing in oral mucosa is faster, associates with a reduced inflammatory response and results to significantly reduced scar formation compared with skin wounds. In the present study, we hypothesized that oral mucosal fibroblasts from human gingiva are inherently distinct from fibroblasts from breast and abdominal skin, two areas prone to excessive scar formation, which may contribute to the preferential wound healing outcome in gingiva. To this end, we compared the phenotype of human gingival and skin fibroblasts cultured in in vivo-like three-dimensional (3D) cultures that mimic the cells' natural extracellular matrix (ECM) niche. To establish 3D cultures, five parallel fibroblast lines from human gingiva (GFBLs) and breast skin (SFBLs) were seeded in high density, and cultured for up to 21 days in serum and ascorbic acid containing medium to induce expression of wound-healing transcriptome and ECM deposition. Cell proliferation, morphology, phenotype and expression of wound healing and scar related genes were analyzed by real-time RT-PCR, Western blotting and immunocytochemical methods. The expression of a set of genes was also studied in three parallel lines of human abdominal SFBLs. Findings showed that GFBLs displayed morphologically distinct organization of the 3D cultures and proliferated faster than SFBLs. GFBLs expressed elevated levels of molecules involved in regulation of inflammation and ECM remodeling (MMPs) while SFBLs showed significantly higher expression of TGF-β signaling, ECM and myofibroblast and cell contractility-related genes. Thus, GFBLs display an inherent phenotype conducive for fast resolution of inflammation and ECM remodeling, characteristic for scar-free wound healing, while SFBLs have a profibrotic, scar-prone phenotype.