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International Journal of Molecular... Feb 2021The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized... (Review)
Review
The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized bone, but also dentine, cementum and enamel of our teeth. These are exposed to intense mechanical and chemical stress as well as to dense microbiologic colonization. Teeth are susceptible to damage, most commonly to caries, where microorganisms from the oral cavity degrade the mineralized tissues of enamel and dentine and invade the soft connective tissue at the core, the dental pulp. However, the pulp is well-equipped to sense and fend off bacteria and their products and mounts various and intricate defense mechanisms. The front rank is formed by a layer of odontoblasts, which line the pulp chamber towards the dentine. These highly specialized cells not only form mineralized tissue but exert important functions as barrier cells. They recognize pathogens early in the process, secrete antibacterial compounds and neutralize bacterial toxins, initiate the immune response and alert other key players of the host defense. As bacteria get closer to the pulp, additional cell types of the pulp, including fibroblasts, stem and immune cells, but also vascular and neuronal networks, contribute with a variety of distinct defense mechanisms, and inflammatory response mechanisms are critical for tissue homeostasis. Still, without therapeutic intervention, a deep carious lesion may lead to tissue necrosis, which allows bacteria to populate the root canal system and invade the periradicular bone via the apical foramen at the root tip. The periodontal tissues and alveolar bone react to the insult with an inflammatory response, most commonly by the formation of an apical granuloma. Healing can occur after pathogen removal, which is achieved by disinfection and obturation of the pulp space by root canal treatment. This review highlights the various mechanisms of pathogen recognition and defense of dental pulp cells and periradicular tissues, explains the different cell types involved in the immune response and discusses the mechanisms of healing and repair, pointing out the close links between inflammation and regeneration as well as between inflammation and potential malignant transformation.
Topics: Animals; Antigens, Neoplasm; Carcinogenesis; Carcinoma, Squamous Cell; Chemokines; Complement System Proteins; Dental Caries; Dental Pulp; Dentin; Fibroblasts; Humans; Intracellular Signaling Peptides and Proteins; Mesenchymal Stem Cells; Mouth Neoplasms; Nerve Net; Neuropeptides; Nitric Oxide; Odontoblasts; Periapical Granuloma; Periapical Periodontitis; Periapical Tissue; Pulpitis; Radicular Cyst
PubMed: 33540711
DOI: 10.3390/ijms22031480 -
Cells Jul 2022BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad... (Review)
Review
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.
Topics: Animals; Bone Morphogenetic Proteins; Dentin; Humans; Mice; Odontoblasts; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 35883659
DOI: 10.3390/cells11142216 -
Cell Communication and Signaling : CCS May 2021Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP...
BACKGROUND
Mitochondrial DNA (mtDNA) is a vital driver of inflammation when it leaks from damaged mitochondria into the cytosol. mtDNA stress may contribute to cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway activation in infectious diseases. Odontoblasts are the first cells challenged by cariogenic bacteria and involved in maintenance of the pulp immune and inflammatory responses to dentine-invading pathogens. In this study, we investigated that mtDNA as an important inflammatory driver participated in defending against bacterial invasion via cGAS-STING pathway in odontoblasts.
METHODS
The normal tissues, caries tissues and pulpitis tissues were measured by western blotting and immunohistochemical staining. Pulpitis model was built in vitro to evaluated the effect of the cGAS-STING pathway in odontoblast-like cell line (mDPC6T) under inflammation. Western blot and real-time PCR were performed to detect the expression of cGAS-STING pathway and pro-inflammatory cytokines. The mitochondrial function was evaluated reactive oxygen species (ROS) generated by mitochondria using MitoSOX Red dye staining. Cytosolic DNA was assessed by immunofluorescent staining and real-time PCR in mDPC6T cells after LPS stimulation. Furthermore, mDPC6T cells were treated with ethidium bromide (EtBr) to deplete mtDNA or transfected with isolated mtDNA. The expression of cGAS-STING pathway and pro-inflammatory cytokines were measured.
RESULTS
The high expression of cGAS and STING in caries and pulpitis tissues in patients, which was associated with inflammatory progression. The cGAS-STING pathway was activated in inflamed mDPC6T. STING knockdown inhibited the nuclear import of p65 and IRF3 and restricted the secretion of the inflammatory cytokines CXCL10 and IL-6 induced by LPS. LPS caused mitochondrial damage in mDPC6T, which promoted mtDNA leakage into the cytosol. Depletion of mtDNA inhibited the cGAS-STING pathway and nuclear translocation of p65 and IRF3. Moreover, repletion of mtDNA rescued the inflammatory response, which was inhibited by STING knockdown.
CONCLUSION
Our study systematically identified a novel mechanism of LPS-induced odontoblast inflammation, which involved mtDNA leakage from damaged mitochondria into the cytosol stimulating the cGAS-STING pathway and the inflammatory cytokines IL-6 and CXCL10 secretion. The mtDNA-cGAS-STING axis could be a potent therapeutic target to prevent severe bacterial inflammation in pulpitis. Video Abstract.
Topics: Cell Line; Cytosol; DNA, Mitochondrial; Dental Caries; Humans; Inflammation; Lipopolysaccharides; Membrane Proteins; Mitochondria; Nucleotidyltransferases; Odontoblasts; Pulpitis; Signal Transduction
PubMed: 34016129
DOI: 10.1186/s12964-021-00738-7 -
Mediators of Inflammation 2015Dental caries is a chronic infectious disease resulting from the penetration of oral bacteria into the enamel and dentin. Microorganisms subsequently trigger... (Review)
Review
Dental caries is a chronic infectious disease resulting from the penetration of oral bacteria into the enamel and dentin. Microorganisms subsequently trigger inflammatory responses in the dental pulp. These events can lead to pulp healing if the infection is not too severe following the removal of diseased enamel and dentin tissues and clinical restoration of the tooth. However, chronic inflammation often persists in the pulp despite treatment, inducing permanent loss of normal tissue and reducing innate repair capacities. For complete tooth healing the formation of a reactionary/reparative dentin barrier to distance and protect the pulp from infectious agents and restorative materials is required. Clinical and in vitro experimental data clearly indicate that dentin barrier formation only occurs when pulp inflammation and infection are minimised, thus enabling reestablishment of tissue homeostasis and health. Therefore, promoting the resolution of pulp inflammation may provide a valuable therapeutic opportunity to ensure the sustainability of dental treatments. This paper focusses on key cellular and molecular mechanisms involved in pulp responses to bacteria and in the pulpal transition between caries-induced inflammation and dentinogenic-based repair. We report, using selected examples, different strategies potentially used by odontoblasts and specialized immune cells to combat dentin-invading bacteria in vivo.
Topics: Animals; Antigens; Cell Differentiation; Dendritic Cells; Dental Caries; Dental Enamel; Dental Pulp; Dentin; Dentin, Secondary; Homeostasis; Humans; Inflammation; Interleukin-10; Interleukin-6; Odontoblasts; T-Lymphocytes, Helper-Inducer; Tooth
PubMed: 26538821
DOI: 10.1155/2015/230251 -
Nature Communications Sep 2020Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of...
Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation.
Topics: Adolescent; Adult; Animals; Cell Differentiation; Epithelial Cells; Female; Gene Expression Regulation, Developmental; Genetic Heterogeneity; Humans; Incisor; Male; Mesoderm; Mice; Mice, Inbred C57BL; Models, Animal; Molar; Odontoblasts; Stem Cells; Tooth; Young Adult
PubMed: 32968047
DOI: 10.1038/s41467-020-18512-7 -
International Journal of Molecular... Jul 2020In vertebrates, biomineralization is a feature considered unique to mature osteoblasts and odontoblasts by which they synthesize hydroxyapatite (HAP), which is deposited...
In vertebrates, biomineralization is a feature considered unique to mature osteoblasts and odontoblasts by which they synthesize hydroxyapatite (HAP), which is deposited in the collagen matrix to construct endoskeleton. For many decades, the mechanisms that modulate differentiation and maturation of these specialized cells have been sought as a key to understanding bone-remodeling defects. Here, we report that biomineralization is an innate ability of all mammalian cells, irrespective of cell type or maturation stage. This innate biomineralization is triggered by the concomitant exposure of living cells to three indispensable elements: calcium ion, phosphoester salt, and alkaline phosphatase. Any given somatic cell, including undifferentiated mononuclear cells, can undergo a biomineralization process to produce calcium-phosphate agglomerates. The biologically generated minerals under such conditions are composed of genuine HAP crystallites of Ca(PO)(OH) and 5-10 nanometer (nm) in size. This discovery will profoundly improve our understanding of bone metabolism and ectopic calcifications.
Topics: Alkaline Phosphatase; Animals; Biomineralization; Bone and Bones; Calcium Phosphates; Cell Differentiation; Cell Line; Cell Line, Tumor; Collagen; Durapatite; HEK293 Cells; HL-60 Cells; HeLa Cells; Humans; K562 Cells; MCF-7 Cells; Mammals; Mice; NIH 3T3 Cells; Odontoblasts; Osteoblasts; PC-3 Cells; THP-1 Cells; U937 Cells
PubMed: 32650435
DOI: 10.3390/ijms21144820 -
Connective Tissue Research Jan 2023Previous studies demonstrated that the exposure of primary dental pulp (DP) cultures to fibroblast growth factor 2 (FGF2) between days 3-7 exerted significant and...
PURPOSE
Previous studies demonstrated that the exposure of primary dental pulp (DP) cultures to fibroblast growth factor 2 (FGF2) between days 3-7 exerted significant and long-lasting stimulatory effects on odontoblast differentiation and expression. These effects involved the increased expression of components of bone morphogenetic protein (BMP) signaling and were reverted by a BMP inhibitor noggin. FGF2 also transiently stimulated osteoblast differentiation and the expression of and . The present study aimed to further explore interactions between BMP and FGF signaling during odontoblast and osteoblast differentiation in DP cultures.
MATERIALS AND METHODS
Cultures were established using DP tissue isolated from non-transgenic and fluorescent reporter (DSPP-Cerulean, BSP-GFP, and DMP1-mCherry) transgenic mice and exposed to BMP2, FGF2, SU5402 (an FGF receptor inhibitor), and noggin between days 3-7. Mineralization, gene expression, fluorescent protein expression, and odontoblast formation were examined using xylenol orange, quantitative PCR, fluorometric analysis, and immunocytochemistry, respectively.
RESULTS
BMP2 activated SMAD1/5/8 but not ERK1/2 signaling, whereas FGF2 exerted opposite effects. BMP2 did not affect mineralization, the expression of and , and the percentage of DSPP-Cerulean+ odontoblasts but significantly increased and DSPP-Cerulean. In cultures exposed to BMP2 and FGF2, respectively, both SU5402 and noggin led to long-lasting decreases in and DSPP-Cerulean and transient decreases in and DMP1-mCherry without affecting and BSP-GFP.
CONCLUSION
BMP2 and FGF2 exerted reciprocal stimulatory effects on odontoblast differentiation, whereas their effects on osteoblast differentiation were mediated independently. These data will further elucidate the perspectives of using BMP2 and FGF2 for dentin regeneration/repair.
Topics: Mice; Animals; Odontoblasts; Fibroblast Growth Factor 2; Mice, Transgenic; Extracellular Matrix Proteins; Cell Differentiation; Signal Transduction; Phosphoproteins; Sialoglycoproteins
PubMed: 35816114
DOI: 10.1080/03008207.2022.2094789 -
Saudi Medical Journal Feb 2018Herbal remedies are used throughout the world, either in earlier or in recent times. The number of studies on this alternative therapeutic system increased in the last... (Review)
Review
Herbal remedies are used throughout the world, either in earlier or in recent times. The number of studies on this alternative therapeutic system increased in the last decades. In this paper, the relevant literature on the use of natural products in root canal therapy is revised from a MEDLINE database search. The uses of medicinal plants in endodontics include cleaning and disinfection of root canals, intracanal medicaments between appointments, sealer cements, and for removal of obturation material. Other studies showed the effect of natural products in pulpal and dentin repair. Their use is anecdotal, and their effectiveness showed to be variable and is always compared to the chemical standards currently being used. Alkaloids, coumarins, saponins, and flavonoids are aromatic substances that are produced by plants and evaluated for their therapeutic potential. Further investigation into benefits of natural products is warranted.
Topics: Biological Products; Endodontics; Humans; Odontoblasts; Root Canal Irrigants; Root Canal Therapy; Smear Layer; Solvents
PubMed: 29436559
DOI: 10.15537/smj.2018.2.21038 -
European Journal of Cell Biology Jan 2019Cell polarity identifies the asymmetry of a cell. Various types of cells, including odontoblasts and epithelial cells, polarize to fulfil their destined functions.... (Review)
Review
Cell polarity identifies the asymmetry of a cell. Various types of cells, including odontoblasts and epithelial cells, polarize to fulfil their destined functions. Odontoblast polarization is a prerequisite and fundamental step for tooth development and tubular dentin formation. Current knowledge of odontoblast polarization, however, is very limited, which greatly impedes the development of novel approaches for regenerative endodontics. Compared to odontoblasts, epithelial cell polarization has been extensively studied over the last several decades. The knowledge obtained from epithelia polarization has been found applicable to other cell types, which is particularly useful considering the remarkable similarities of the morphological and compositional features between polarized odontoblasts and epithelia. In this review, we first discuss the characteristics, the key regulatory factors, and the process of epithelial polarity. Next, we compare the known facts of odontoblast polarization with epithelial cells. Lastly, we clarify knowledge gaps in odontoblast polarization and propose the directions for future research to fill the gaps, leading to the advancement of regenerative endodontics.
Topics: Animals; Cell Polarity; Epithelial Cells; Models, Biological; Odontoblasts; rho GTP-Binding Proteins
PubMed: 30473389
DOI: 10.1016/j.ejcb.2018.11.003