Molecular Mechanisms of Dentine-Pulp Complex Response Induced by Microbiome of Deep Caries

Abstract Deep caries progress is associated with tertiary dentin formation and additional reversible or irreversible dental pulp inflammation. It seems that some particular signs of pain in irreversible pulpitis are associated to a particular caries microflora. Streptococcus species, Parvimonas micra and Dialister invisus are prevailing in cases of throbbing pain while Streptococcus mutans is incriminated in sensitivity to vertical percussion of tooth. Continuous pain is thought to be the clinical outcome of Lactobacillus implication. A better understanding of molecular signals and mechanisms induced by microbiome of deep caries that orchestrate the modulation of dental pulp complex response toward tertiary dentinogenesis or pulp inflammation it is supposed to improve diagnosis and conservative therapies of vital pulp.

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Reactionary Versus Reparative Dentine in Deep Caries

ARS Medica Tomitana ◽

10.2478/arsm-2019-0004 ◽

2019 ◽

Vol 25 (1) ◽

pp. 15-21

Author(s):

Iliescu Alexandru-Andrei ◽

Gheorghiu Irina-Maria ◽

Tănase Mihaela ◽

Iliescu Andrei ◽

Mitran Loredana ◽

...

Keyword(s):

Stem Cells ◽

Dental Pulp ◽

Dental Pulp Stem Cells ◽

Complex Response ◽

Pulp Inflammation ◽

Proliferation And Differentiation ◽

Molecular Signals

Abstract The dentine-pulp complex response in deep caries is histological characterized by tertiary formation and mild chronic pulp inflammation. The quiescent primary odontoblasts are reactivated, laying down reactionary tertiary dentine. In more severe carious damage the primary odontoblasts die and reparative tertiary dentine is secreted by odontoblast-like cells, which are differentiated in adult teeth mainly from dental pulp stem cells DPSC. Though associated with reversible pulpitis DPSC still preserve in deep caries the capability of migration, proliferation and differentiation. Some common mechanisms of molecular signals involved in tertiary dentine formation might also explain the balance between inflammation and regeneration of dentine-pulp complex.

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Surface Pre-Reacted Glass Filler Contributes to Tertiary Dentin Formation through a Mechanism Different Than That of Hydraulic Calcium-Silicate Cement

Journal of Clinical Medicine ◽

10.3390/jcm8091440 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1440 ◽

Cited By ~ 2

Author(s):

Motoki Okamoto ◽

Manahil Ali ◽

Shungo Komichi ◽

Masakatsu Watanabe ◽

Hailing Huang ◽

...

Keyword(s):

Gene Expression ◽

Calcium Silicate ◽

Dental Pulp ◽

Healing Process ◽

Calcium Silicate Cement ◽

Tertiary Dentin ◽

Regulated Gene Expression ◽

Dentin Formation ◽

Hydraulic Calcium Silicate Cement

The induction of tissue mineralization and the mechanism by which surface pre-reacted glass-ionomer (S-PRG) cement influences pulpal healing remain unclear. We evaluated S-PRG cement-induced tertiary dentin formation in vivo, and its effect on the pulp cell healing process in vitro. Induced tertiary dentin formation was evaluated with micro-computed tomography (μCT) and scanning electron microscopy (SEM). The distribution of elements from the S-PRG cement in pulpal tissue was confirmed by micro-X-ray fluorescence (μXRF). The effects of S-PRG cement on cytotoxicity, proliferation, formation of mineralized nodules, and gene expression in human dental pulp stem cells (hDPSCs) were assessed in vitro. μCT and SEM revealed that S-PRG induced tertiary dentin formation with similar characteristics to that induced by hydraulic calcium-silicate cement (ProRoot mineral trioxide aggregate (MTA)). μXRF showed Sr and Si ion transfer into pulpal tissue from S-PRG cement. Notably, S-PRG cement and MTA showed similar biocompatibility. A co-culture of hDPSCs and S-PRG discs promoted mineralized nodule formation on surrounding cells. Additionally, S-PRG cement regulated the expression of genes related to osteo/dentinogenic differentiation. MTA and S-PRG regulated gene expression in hDPSCs, but the patterns of regulation differed. S-PRG cement upregulated CXCL-12 and TGF-β1 gene expression. These findings showed that S-PRG and MTA exhibit similar effects on dental pulp through different mechanisms.

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Presence or Absence of Tertiary Dentinogenesis in Relation to Caries Progression

Advances in Dental Research ◽

10.1177/08959374010150012101 ◽

2001 ◽

Vol 15 (1) ◽

pp. 80-83 ◽

Cited By ~ 24

Author(s):

L. Bjørndal

Keyword(s):

Hard Tissue ◽

Very Old ◽

Tertiary Dentin ◽

Tissue Responses ◽

Caries Progression ◽

Dentin Formation ◽

Caries Lesions ◽

Over Time ◽

Tertiary Dentinogenesis ◽

Cavitated Lesions

Studies have shown that dental caries may or may not be associated with tertiary dentin formation in the pulp. On the basis of histological examinations of 69 clinical well-defined caries lesions, a hypothesis is proposed on the dynamics of the hard-tissue responses of the pulp to caries. In active non-cavitated lesions, the formation of tertiary dentin seems to be initiated by primary odontoblast cells that subsequently result in atubular dentin/fibrodentinogenesis, whereas, in similarly aged but more rapidly progressing cavitated enamel lesions, no tertiary dentin is laid down by primary odontoblast cells. In all old-dentin exposed lesions, a so-called closed lesion environment was defined with subjacent atubular dentin formation. As these lesions progress, a shift from a closed to a more large and open lesion environment may develop in the very old lesions, and a new tubular dentinal matrix is noted on the top of the fibrodentin, also defined as reparative dentinogenesis. In very old slowly progressing lesions, a relatively small open lesion environment is also observed, with tubular tertiary dentin resembling the primary dentin being strictly tubular. It is suggested that the absence of tertiary dentinogenesis can be expected in very rapid caries lesions, whereas a variety of tertiary dentin is observed in older dentin cavitated lesions guided by a changing external lesion environment over time.

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Dental Pulp Defence and Repair Mechanisms in Dental Caries

Mediators of Inflammation ◽

10.1155/2015/230251 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 100

Author(s):

Jean-Christophe Farges ◽

Brigitte Alliot-Licht ◽

Emmanuelle Renard ◽

Maxime Ducret ◽

Alexis Gaudin ◽

...

Keyword(s):

Dental Caries ◽

Dental Pulp ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Oral Bacteria ◽

Barrier Formation ◽

Reparative Dentin ◽

Pulp Inflammation

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 andin vitroexperimental 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 bacteriain vivo.

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Further Observations on Tertiary Dentin in Human Deciduous Teeth

Advances in Dental Research ◽

10.1177/08959374010150011901 ◽

2001 ◽

Vol 15 (1) ◽

pp. 76-79 ◽

Cited By ~ 10

Author(s):

Randi Furseth Klinge

Keyword(s):

Organic Matrix ◽

Deciduous Teeth ◽

Pulp Chamber ◽

Hard Tissue ◽

Root Canals ◽

Tertiary Dentin ◽

Reparative Dentin ◽

Pulp Inflammation ◽

Dentin Formation ◽

New Generation

The structure of reparative tertiary dentin in human deciduous teeth has been studied. Reparative dentin is secreted by a new generation of odontoblast-like cells which have been subject to strong stimuli, e.g., trauma or deep active caries lesions with associated pulp inflammation. Ground sections of 25 teeth were prepared, and contact microradiographs were produced. Another 30 teeth were demineralized, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Some demineralized sections from each tooth were also studied in the scanning electron microscope. Most of the teeth showed some type of tertiary dentin formation. Mineralized tissue with a varied morphology was observed. In teeth which had been subject to trauma, the entire pulp chamber was sometimes obliterated. Mineralization seemed to start in the incisal region, and the central part of the pulp was the last part to be obliterated. Radiolucent voids and canals were seen. The organic matrix was dense and fibrous. In the pulp chamber and especially in the root canals, resorption had often occurred, indicating that signals giving rise to odontoclasts were also present. Resorption was often followed by deposition of various amounts of cementum-like repair tissue. The cells responsible for the formation of reparative dentin are believed to be subodontoblasts or undifferentiated ectomesenchymal cells. The varied morphology of the reparative dentin, observed in the pulp of the teeth examined, indicates that different stimuli lead to induction of hard-tissue-forming cells which produce different types of hard tissue.

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Midkine Promotes Odontoblast-like Differentiation and Tertiary Dentin Formation

Journal of Dental Research ◽

10.1177/0022034520925427 ◽

2020 ◽

Vol 99 (9) ◽

pp. 1082-1091 ◽

Cited By ~ 1

Author(s):

Y.H. Park ◽

Y.S. Lee ◽

Y.M. Seo ◽

H. Seo ◽

J.S. Park ◽

...

Keyword(s):

Cell Differentiation ◽

Dental Pulp ◽

Expression Patterns ◽

Exposure Model ◽

Tooth Pulp ◽

Dental Pulp Cells ◽

Tertiary Dentin ◽

Pulp Cells ◽

Dentin Formation

Autophagy is an intracellular self-degradation process that is essential for tissue development, cell differentiation, and survival. Nevertheless, the role of autophagy in tooth development has not been definitively identified. The goal of this study was to investigate how autophagy is involved in midkine (MK)–mediated odontoblast-like differentiation, mineralization, and tertiary dentin formation in a mouse tooth pulp exposure model. In vitro studies show that MK and LC3 have similar expression patterns during odontoblast-like cell differentiation. Odontoblast-like cell differentiation is promoted through MK-mediated autophagy, which leads to increased mineralized nodule formation. Subcutaneous transplantation of hydroxyapatite/tricalcium phosphate with rMK-treated human dental pulp cells led to dentin pulp–like tissue formation through MK-mediated autophagy. Furthermore, MK-mediated autophagy induces differentiation of dental pulp cells into odontoblast-like cells that form DSP-positive tertiary dentin in vivo. Our findings may provide 1) novel insight into the role of MK in regulating odontoblast-like differentiation and dentin formation in particular via autophagy and 2) potential application of MK in vital pulp therapy.

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Immunomodulatory Expression of Cathelicidins Peptides in Pulp Inflammation and Regeneration: An Update

Current Issues in Molecular Biology ◽

10.3390/cimb43010010 ◽

2021 ◽

Vol 43 (1) ◽

pp. 116-126

Author(s):

Nireeksha ◽

Sudhir Rama Varma ◽

Marah Damdoum ◽

Mohammed Amjed Alsaegh ◽

Mithra N. Hegde ◽

...

Keyword(s):

Cell Differentiation ◽

Dental Pulp ◽

Secretory Activity ◽

Local Environment ◽

Innate Immune ◽

Reparative Dentin ◽

Pulp Inflammation ◽

Dentin Formation ◽

Immunomodulatory Potential

The role of inflammatory mediators in dental pulp is unique. The local environment of pulp responds to any changes in the physiology that are highly fundamental, like odontoblast cell differentiation and other secretory activity. The aim of this review is to assess the role of cathelicidins based on their capacity to heal wounds, their immunomodulatory potential, and their ability to stimulate cytokine production and stimulate immune-inflammatory response in pulp and periapex. Accessible electronic databases were searched to find studies reporting the role of cathelicidins in pulpal inflammation and regeneration published between September 2010 and September 2020. The search was performed using the following databases: Medline, Scopus, Web of Science, SciELO and PubMed. The electronic search was performed using the combination of keywords “cathelicidins” and “dental pulp inflammation”. On the basis of previous studies, it can be inferred that LL-37 plays an important role in odontoblastic cell differentiation and stimulation of antimicrobial peptides. Furthermore, based on these outcomes, it can be concluded that LL-37 plays an important role in reparative dentin formation and provides signaling for defense by activating the innate immune system.

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Evaluating the potential of an amelogenin-derived peptide in tertiary dentin formation

Regenerative Biomaterials ◽

10.1093/rb/rbab004 ◽

2021 ◽

Vol 8 (2) ◽

Author(s):

Xiu Peng ◽

Sili Han ◽

Kun Wang ◽

Longjiang Ding ◽

Zhenqi Liu ◽

...

Keyword(s):

Cell Viability ◽

Dental Pulp ◽

Cell Counting ◽

Control Group ◽

Micro Computed Tomography ◽

Alizarin Red ◽

Pulp Capping ◽

Tertiary Dentin ◽

Dental Pulp Capping ◽

Dentin Formation

Abstract Several novel biomaterials have been developed for dental pulp capping by inducing tertiary dentin formation. The aim of this study was to evaluate the effect of QP5, an amelogenin-based peptide, on the mineralization of dental pulp cells (DPCs) in vitro and in vivo. The cell viability of human DPCs (hDPCs) after treatment with QP5 was determined using the Cell Counting Kit-8 (CCK-8). Migration of hDPCs was assessed using scratch assays, and the pro-mineralization effect was determined using alkaline phosphatase (ALP) staining, alizarin red staining and the expression of mineralization-related genes and proteins. The results showed that QP5 had little effect on the cell viability, and significantly enhanced the migration capability of hDPCs. QP5 promoted the formation of mineralized nodules, and upregulated the activity of ALP, the expression of mRNA and proteins of mineralization-related genes. A pulp capping model in rats was generated to investigate the biological effect of QP5. The results of micro-computed tomography and haematoxylin and eosin staining indicated that the formation of tertiary dentin in QP5-capping groups was more prominent than that in the negative control group. These results indicated the potential of QP5 as a pulp therapy agent.

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Effect of a Calcium-silicate-based Restorative Cement on Pulp Repair

Journal of Dental Research ◽

10.1177/0022034512460833 ◽

2012 ◽

Vol 91 (12) ◽

pp. 1166-1171 ◽

Cited By ~ 110

Author(s):

X.V. Tran ◽

C. Gorin ◽

C. Willig ◽

B. Baroukh ◽

B. Pellat ◽

...

Keyword(s):

Calcium Silicate ◽

Glass Ionomer Cement ◽

Repair Process ◽

Male Rats ◽

Time Points ◽

Tertiary Dentin ◽

Pulp Exposure ◽

Calcium Silicate Cements ◽

Reparative Process ◽

Dentin Formation

In cases of pulp injury, capping materials are used to enhance tertiary dentin formation; Ca(OH)2 and MTA are the current gold standards. The aim of this study was to evaluate the capacity of a new calcium-silicate-based restorative cement to induce pulp healing in a rat pulp injury model. For that purpose, cavities with mechanical pulp exposure were prepared on maxillary first molars of 27 six-week-old male rats, and damaged pulps were capped with either the new calcium-silicate-based restorative cement (Biodentine), MTA, or Ca(OH)2. Cavities were sealed with glass-ionomer cement, and the repair process was assessed at several time-points. At day 7, our results showed that both the evaluated cement and MTA induced cell proliferation and formation of mineralization foci, which were strongly positive for osteopontin. At longer time-points, we observed the formation of a homogeneous dentin bridge at the injury site, secreted by cells displaying an odontoblastic phenotype. In contrast, the reparative tissue induced by Ca(OH)2 showed porous organization, suggesting a reparative process different from those induced by calcium silicate cements. Analysis of these data suggests that the evaluated cement can be used for direct pulp-capping.

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Resolvin E1 accelerates pulp repair by regulating inflammation and stimulating dentin regeneration in dental pulp stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02141-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jie Chen ◽

Huaxing Xu ◽

Kun Xia ◽

Shuhua Cheng ◽

Qi Zhang

Keyword(s):

Dental Pulp ◽

Tissue Repair ◽

Pulp Tissue ◽

Tissue Repair And Regeneration ◽

Injury Model ◽

Tnf Α ◽

Pulp Inflammation ◽

Inflammation Resolution ◽

Pulp Repair ◽

Dentin Regeneration

Abstract Background Unresolved inflammation and tissue destruction are considered to underlie the failure of dental pulp repair. As key mediators of the injury response, dental pulp stem cells (DPSCs) play a critical role in pulp tissue repair and regeneration. Resolvin E1 (RvE1), a major dietary omega-3 polyunsaturated fatty-acid metabolite, is effective in resolving inflammation and activating wound healing. However, whether RvE1 facilitates injured pulp-tissue repair and regeneration through timely resolution of inflammation and rapid mobilization of DPSCs is unknown. Therefore, we established a pulp injury model and investigated the effects of RvE1 on DPSC-mediated inflammation resolution and injured pulp repair. Methods A pulp injury model was established using 8-week-old Sprague-Dawley rats. Animals were sacrificed on days 1, 3, 7, 14, 21, and 28 after pulp capping with a collagen sponge immersed in PBS with RvE1 or PBS. Hematoxylin-eosin and Masson’s trichrome staining, immunohistochemistry, and immunohistofluorescence were used to evaluate the prohealing properties of RvE1. hDPSCs were incubated with lipopolysaccharide (LPS) to induce an inflammatory response, and the expression of inflammatory factors after RvE1 application was measured. Effects of RvE1 on hDPSC proliferation, chemotaxis, and odontogenic differentiation were evaluated by CCK-8 assay, transwell assay, alkaline phosphatase (ALP) staining, alizarin red staining, and quantitative PCR, and possible signaling pathways were explored using western blotting. Results In vivo, RvE1 reduced the necrosis rate of damaged pulp and preserved more vital pulps, and promoted injured pulp repair and reparative dentin formation. Further, it enhanced dentin matrix protein 1 and dentin sialoprotein expression and accelerated pulp inflammation resolution by suppressing TNF-α and IL-1β expression. RvE1 enhanced the recruitment of CD146+ and CD105+ DPSCs to the damaged molar pulp mesenchyme. Isolated primary cells exhibited the mesenchymal stem cell immunophenotype and differentiation. RvE1 promoted hDPSC proliferation and chemotaxis. RvE1 significantly attenuated pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and enhanced ALP activity, nodule mineralization, and especially, expression of the odontogenesis-related genes DMP1, DSPP, and BSP in LPS-stimulated DPSCs. RvE1 regulated AKT, ERK, and rS6 phosphorylation in LPS-stimulated DPSCs. Conclusions RvE1 promotes pulp inflammation resolution and dentin regeneration and positively influences the proliferation, chemotaxis, and differentiation of LPS-stimulated hDPSCs. This response is, at least partially, dependent on AKT, ERK, and rS6-associated signaling in the inflammatory microenvironment. RvE1 has promising application potential in regenerative endodontics.

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