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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 -
Journal of Endodontics Nov 2021Although many clinical studies have reported on the prevalence of dental pain, far fewer studies have focused on the mechanisms of dental pain. This is an important gap... (Review)
Review
INTRODUCTION
Although many clinical studies have reported on the prevalence of dental pain, far fewer studies have focused on the mechanisms of dental pain. This is an important gap because increased understanding of dental pain mechanisms may lead to improved diagnostic tests or therapeutic interventions. The aim of this study was to comprehensively review the literature on the mechanisms of dentinal sensitivity.
METHODS
PubMed and Ovid were searched for articles that addressed dentinal pain and or pulpal sensitivity. Because of the breadth of research ranging from cellular/molecular studies to clinical trials, a narrative review on the mechanisms of dentinal sensitivity was constructed based on the literature.
RESULTS
Five various mechanisms for dentinal sensitivity have been proposed: (1) the classic hydrodynamic theory, (2) direct innervation of dentinal tubules, (3) neuroplasticity and sensitization of nociceptors, (4) odontoblasts serving as sensory receptors, and (5) algoneurons.
CONCLUSIONS
These theories are not mutually exclusive, and it is possible that several of them contribute to dentinal sensitivity. Moreover, pulpal responses to tissue injury may alter the relative contribution of these mechanisms. For example, pulpal inflammation may lead to neuronal sprouting and peripheral sensitization. Knowledge of these mechanisms may prompt the development of therapeutic drugs that aim to disrupt these mechanisms, leading to more effective treatments for pulpal pain.
Topics: Dental Pulp; Dentin; Dentin Sensitivity; Humans; Nociceptors; Odontoblasts; Pain
PubMed: 34302871
DOI: 10.1016/j.joen.2021.07.011 -
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 -
Journal of Cellular Physiology Apr 2022Retraction: "Downregulated microRNA-488 enhances odontoblast differentiation of human dental pulp stem cells via activation of the p38 MAPK signaling pathway," by Dan...
Retraction: "Downregulated microRNA-488 enhances odontoblast differentiation of human dental pulp stem cells via activation of the p38 MAPK signaling pathway," by Dan Yu, Xue Zhao, Jin-Zhang Cheng, Di Wang, Hui-Hui Zhang, and Guang-Hong Han, J Cell Physiol. 2019; 1442-1451: The above article, published online on 21 August 2018 in Wiley Online Library (https://doi.org/10.1002/jcp.26950) has been retracted by agreement between the the authors, journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed after the authors asked to correct the article. An investigation revealed several flaws and inconsistencies between results presented and experimental methods described, thus the editors consider the conclusions of this article to be invalid.
PubMed: 34873705
DOI: 10.1002/jcp.30635 -
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 -
Journal of the American Dental... Dec 2023Stem cells are present in most of the tissues in the craniofacial complex and play a major role in tissue homeostasis and repair. These cells are characterized by their... (Review)
Review
BACKGROUND
Stem cells are present in most of the tissues in the craniofacial complex and play a major role in tissue homeostasis and repair. These cells are characterized by their capacity to differentiate into multiple cell types and to self-renew to maintain a stem cell pool throughout the life of the tissue.
TYPES OF STUDIES REVIEWED
The authors discuss original data from experiments and comparative analyses and review articles describing the identification and characterization of stem cells of the oral cavity.
RESULTS
Every oral tissue except enamel, dentin, and cementum contains stem cells for the entire life span. These stem cells self-renew to maintain a pool of cells that can be activated to replace terminally differentiated cells (for example, odontoblasts) or to enable wound healing (for example, dentin bridge in pulp exposures and healing of periodontal tissues after surgery). In addition, dental stem cells can differentiate into functional blood vessels and nerves. Initial clinical trials have shown that transplanting dental pulp stem cells into disinfected necrotic teeth has allowed for the recovery of tooth vitality and vertical and horizontal root growth in immature teeth with incomplete root formation.
PRACTICAL IMPLICATIONS
As a consequence of these groundbreaking discoveries, stem cell banks are now offering services for the cryopreservation of dental stem cells. The future use of stem cell-based therapies in the clinic will depend on the collaboration of clinicians and researchers in projects designed to understand whether these treatments are safe, efficacious, and clinically feasible.
Topics: Humans; Dental Pulp; Tissue Engineering; Stem Cells; Tooth; Dentistry
PubMed: 37804275
DOI: 10.1016/j.adaj.2023.08.007 -
Cell Proliferation Sep 2023Mitochondrial transfer is emerging as a promising therapeutic strategy for tissue repair, but whether it protects against pulpitis remains unclear. Here, we show that...
Mitochondrial transfer is emerging as a promising therapeutic strategy for tissue repair, but whether it protects against pulpitis remains unclear. Here, we show that hyperactivated nucleotide-binding domain and leucine-rich repeat protein3 (NLRP3) inflammasomes with pyroptotic cell death was present in pulpitis tissues, especially in the odontoblast layer, and mitochondrial oxidative stress (OS) was involved in driving this NLRP3 inflammasome-induced pathology. Using bone marrow mesenchymal stem cells (BMSCs) as mitochondrial donor cells, we demonstrated that BMSCs could donate their mitochondria to odontoblasts via tunnelling nanotubes (TNTs) and, thus, reduce mitochondrial OS and the consequent NLRP3 inflammasome-induced pyroptosis in odontoblasts. These protective effects of BMSCs were mostly blocked by inhibitors of the mitochondrial function or TNT formation. In terms of the mechanism of action, TNF-α secreted from pyroptotic odontoblasts activates NF-κB signalling in BMSCs via the paracrine pathway, thereby promoting the TNT formation in BMSCs and enhancing mitochondrial transfer efficiency. Inhibitions of NF-κB signalling and TNF-α secretion in BMSCs suppressed their mitochondrial donation capacity and TNT formation. Collectively, these findings demonstrated that TNT-mediated mitochondrial transfer is a potential protective mechanism of BMSCs under stress conditions, suggesting a new therapeutic strategy of mitochondrial transfer for dental pulp repair.
Topics: Humans; Pyroptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B; Tumor Necrosis Factor-alpha; Pulpitis; Dental Pulp; Mitochondria
PubMed: 37086012
DOI: 10.1111/cpr.13442 -
FASEB Journal : Official Publication of... Feb 2021The objectives of our study were to investigate the roles of mTORC1 in odontoblast proliferation and mineralization and to determine the mechanism by which mTORC1...
The objectives of our study were to investigate the roles of mTORC1 in odontoblast proliferation and mineralization and to determine the mechanism by which mTORC1 regulates odontoblast mineralization. In vitro, MDPC23 cells were treated with rapamycin (10 nmol/L) and transfected with a lentivirus for short hairpin (shRNA)-mediated silencing of the tuberous sclerosis complex (shTSC1) to inhibit and activate mTORC1, respectively. CCK8 assays, flow cytometry, Alizarin red S staining, ALP staining, qRT-PCR, and western blot analysis were performed. TSC1-conditional knockout (DMP1-Cre ; TSC1 , hereafter CKO) mice and littermate control (DMP1-Cre ; TSC1 , hereafter WT) mice were generated. H&E staining, immunofluorescence, and micro-CT analysis were performed. Transcriptome sequencing analysis was used to screen the mechanism of this process. mTORC1 inactivation decreased the cell proliferation. The qRT-PCR and western blot results showed that mineralization-related genes and proteins were downregulated in mTORC1-inactivated cells. Moreover, mTORC1 overactivation promoted cell proliferation and mineralization-related gene and protein expression. In vivo, the micro-CT results showed that DV/TV and dentin thickness were higher in CKO mice than in controls and H&E staining showed the same results. Mineralization-related proteins expression was upregulated. Transcriptome sequencing analysis revealed that p53 pathway-associated genes were differentially expressed in TSC1-deficient cells. By inhibiting p53 alone or both mTORC1 and p53 with rapamycin and a p53 inhibitor, we elucidated that p53 acts downstream of mTORC1 and that mTORC1 thereby promotes odontoblast mineralization. Taken together, our findings demonstrate that the role of mTORC1 in odontoblast proliferation and mineralization, and confirm that mTORC1 upregulates odontoblast mineralization via the p53 pathway.
Topics: Animals; Cell Line; Cell Proliferation; Dentin; Mechanistic Target of Rapamycin Complex 1; Mice; Odontoblasts; Tooth Calcification; Transcriptome; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Protein p53
PubMed: 33508145
DOI: 10.1096/fj.202002016R