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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 -
Acta Biomaterialia May 2021Angiogenesis is critical for tissue healing and regeneration. Promoting angiogenesis in materials implanted within dental pulp after pulpectomy is a major clinical...
Angiogenesis is critical for tissue healing and regeneration. Promoting angiogenesis in materials implanted within dental pulp after pulpectomy is a major clinical challenge in endodontics. We demonstrate the ability of acellular self-assembling peptide hydrogels to create extracellular matrix mimetic architectures that guide in vivo development of neovasculature and tissue deposition. The hydrogels possess facile injectability, as well as sequence-level functionalizability. We explore the therapeutic utility of an angiogenic hydrogel to regenerate vascularized pulp-like soft tissue in a large animal (canine) orthotopic model. The regenerated soft tissue recapitulates key features of native pulp, such as blood vessels, neural filaments, and an odontoblast-like layer next to dentinal tubules. Our study establishes angiogenic peptide hydrogels as potent scaffolds for promoting soft tissue regeneration in vivo. STATEMENT OF SIGNIFICANCE: A major challenge to endodontic tissue engineering is the lack of in situ angiogenesis within intracanal implants, especially after complete removal of the dental pulp. The lack of a robust vasculature in implants limit integration of matrices with the host tissue and regeneration of soft tissue. We demonstrate the development of an acellular material that promotes tissue revascularization in vivo without added growth factors, in a preclinical canine model of pulp-like soft-tissue regeneration. Such acellular biomaterials would facilitate pulp revascularization approaches in large animal models, and translation into human clinical trials.
Topics: Animals; Biocompatible Materials; Dental Pulp; Extracellular Matrix; Humans; Hydrogels; Tissue Engineering; Tissue Scaffolds
PubMed: 33689817
DOI: 10.1016/j.actbio.2021.03.001 -
Journal of Endodontics Jan 2023The conventional treatment for irreversibly inflamed or necrotic teeth is root canal treatment or apexification. Regenerative endodontics aims to regenerate the damaged... (Review)
Review
INTRODUCTION
The conventional treatment for irreversibly inflamed or necrotic teeth is root canal treatment or apexification. Regenerative endodontics aims to regenerate the damaged "pulp-like" tissue, which can preserve the teeth' vitality and sensitivity while avoiding necrosis. The main clinical benefit is root maturation. The "pulp-like" tissue does not refer to regenerated pulp tissue with an odontoblastic layer or the formation of pulp-dentin complexes. The cell homing technique is built on endogenous stem cells and their capacity to regenerate tissue. Cell homing refers to endogenous cells' migration or infiltration into the cite when stimulated by physiochemical or biological stimuli or by passive flow with a blood clot from the apical tissue. Its Regenerative Endodontic Procedures success criteria are defined by the American Association of Endodontists. The purpose of this article is to provide an overview of vital pulp tissue and various strategies to promote regeneration of damaged pulp tissue. The cell homing technique will be reviewed through clinical trials.
METHODS
We performed a comprehensive literature review on a total of nine clinical trials of regenerative endodontics using the cell-homing technique based on three databases and duplicate manuscripts were removed.
RESULTS
Regenerative endodontics using the cell-homing technique shows promising results that can be translated into clinical practice. However, a favorable result was observed in immature teeth, and the results are contradictory in mature teeth.
CONCLUSION
Regeneration therapy is an attractive new alternative to conventional endodontic treatments. Preservation of vitality and continuation of root development in damaged teeth would be a clear advantage.
Topics: Humans; Regenerative Endodontics; Dental Pulp Necrosis; Tooth Apex; Apexification; Dental Pulp; Root Canal Therapy; Regeneration; Endodontics
PubMed: 36270575
DOI: 10.1016/j.joen.2022.09.008 -
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 -
Central-European Journal of Immunology 2020Eating food is one of the most complicated behaviours in mammals, especially humans. The primary function of ghrelin is regulation of the appetite level and its... (Review)
Review
Eating food is one of the most complicated behaviours in mammals, especially humans. The primary function of ghrelin is regulation of the appetite level and its stimulation. It is also responsible for the body's energy balance and glucose homeostasis. Ghrelin has been shown to affect many brain structures, which confirms the presence of ghrelin receptors in the brain. Studies are also conducted to assess the possible role of ghrelin in anxiety states and in memory disorders and motor dysfunctions. Ghrelin has been found in saliva and salivary glands, teeth and gums, and in the taste buds of the tongue epithelium; it is also secreted by mucosal cells and gingival fibroblasts. The presence of ghrelin in developmental enamel, especially in odontoblasts and ameloblasts, may suggest its regulatory role in the development of teeth. Patients with chronic periodontitis have significantly higher concentrations of ghrelin in the peripheral blood serum, as compared to the control group. Ghrelin plays a special role in the proliferation of cancer cells and in the development of neoplastic metastases. The abundant presence of ghrelin receptors in cancer cells is considered an important target in the treatment of neoplasms. Ghrelin is a hormone whose multidirectional mechanism of action has not yet been fully understood. However, its ubiquitous occurrence in the human body and its very diverse participation in metabolic processes may prove to be a significant obstacle in achieving the expected clinical effect of ghrelin as an effective drug in selected disease units.
PubMed: 33613094
DOI: 10.5114/ceji.2020.103415 -
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