Modulating stemness of mesenchymal stem cells from exfoliated deciduous and permanent teeth by IL-17 and bFGF.

Mesenchymal stem cells (MSCs) have been identified within dental pulp tissues of exfoliated deciduous (SHEDs) and permanent (DPSCs) teeth. Although differences in their proliferative and differentiation properties were revealed, variability in SHEDs and DPSCs responsiveness to growth factors and cytokines have not been studied before. Here, we investigated the influence of interleukin-17 (IL-17) and basic fibroblast growth factor (bFGF) on stemness features of SHEDs and DPSCs by analyzing their proliferation, clonogenicity, cell cycle progression, pluripotency markers expression and differentiation after 7-day treatment. Results indicated that IL-17 and bFGF differently affected SHEDs and DPSCs proliferation and clonogenicity, since bFGF increased proliferative and clonogenic potential of both cell types, while IL-17 similarly affected SHEDs, exerting no effects on adult counterparts DPSCs. In addition, both factors stimulated NANOG, OCT4, and SOX2 pluripotency markers expression in SHEDs and DPSCs showing diverse intracellular expression patterns dependent on MSCs type. As for the differentiation capacity, both factors displayed comparable effects on SHEDs and DPSCs, including stimulatory effect of IL-17 on early osteogenesis in contrast to the strong inhibitory effect showed for bFGF, while having no impact on SHEDs and DPSCs chondrogenesis. Moreover, bFGF combined with IL-17 reduced CD90 and stimulated CD73 expression on both types of MSCs, whereas each factor induced IL-6 expression indicating its' role in IL-17/bFGF-modulated properties of SHEDs and DPSCs. All these data demonstrated that dental pulp MSCs from primary and permanent teeth exert intrinsic features, providing novel evidence on how IL-17 and bFGF affect stem cell properties important for regeneration of dental pulp at different ages.

Tumor Necrosis Factor Alpha -308 G/A Single-Nucleotide Polymorphism and Apical Periodontitis: An Updated Systematic Review and Meta-analysis.

INTRODUCTION: This study aimed to perform a more precise estimation of the association between tumor necrosis factor alpha (TNF-α) -308 G/A single-nucleotide polymorphism (SNP) and the risk of development of apical periodontitis (AP) and its phenotypes based on all available published studies. METHODS: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and is registered in PROSPERO (CRD42020176190). The literature search was conducted via Clarivate Analytics Web of Science, Scopus, PubMed, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure databases from inception to December 2020 with no language restrictions. Two reviewers were involved independently in the study selection, data extraction, and appraising the studies that were included. The quality of the included studies was evaluated using the Strengthening the Reporting of Genetic Association and the Grading of Recommendations Assessment, Development and Evaluation system. The frequencies of the genotypes and alleles of the TNF-α (G>A 308, rs1800629) gene with 95% odds ratio were used. RESULTS: Four studies met the inclusion criteria with moderate risk of bias. This study revealed no significant association between TNF-α -308 G/A SNP and AP and the risk of AP development. Moreover, there was no significant association between genotype or allele frequency distribution and clinical manifestations (acute vs chronic) of AP. The certainty of evidence per the Grading of Recommendations Assessment, Development and Evaluation system was very low. CONCLUSIONS: Because of very low certainty of evidence, whether there is an association between TNF-α -308 G/A SNP and AP warrants further well-designed multicentric studies to adjudicate a better understanding of the role of genetic factors in the etiopathogenesis of AP.

Notch - a possible mediator between Epstein-Barr virus infection and bone resorption in apical periodontitis.

Objectives: This study aimed to investigate whether Epstein-Barr virus (EBV) positive periapical lesions exhibited higher mRNA levels of Notch signalling molecules (Notch2 and Jagged1), bone resorption regulators (receptor activator of nuclear factor kappa-ß ligand (RANKL) and osteoprotegerin (OPG)), and proinflammatory cytokines (tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-6) compared to EBV negative lesions. Additionally, the potential correlation between investigated molecules in periapical lesions was analyzed.Materials and methods: Sixty-four apical periodontitis lesions were obtained subsequent to standard apicoectomy procedure. The presence of EBV was determined using nested PCR. Based on the presence of EBV all periapical lesions were divided into two groups, 29 EBV positive and 35 EBV negative lesions. A reverse transcriptase real-time PCR was used to determine mRNA levels of Notch2, Jagged1, RANKL, OPG, TNF-α, IL-1ß and IL-6.Results: Significantly higher mRNA levels of Notch2, Jagged1, RANKL and IL-1ß were observed in EBV positive compared to EBV negative lesions. Significant positive correlation was present between Notch2 and Jagged1, Jagged1 and RANKL, and IL-ß and TNF-α in EBV positive periapical lesions.Conclusions: Notch signalling pathway may be involved in alveolar bone resorption in apical periodontitis lesions infected by EBV.

Notch signaling pathway mediates alveolar bone resorption in apical periodontitis.

Apical periodontitis represents a chronic inflammatory process within periapical tissues, mostly caused by etiological agents of endodontic origin. Progressive bone resorption in the periapical region represents the hallmark of apical periodontitis and occurs as the consequence of interplay between polymicrobial infections and host response. The Notch signaling pathway is an evolutionary conserved cell-signaling system that plays an important role in a variety of cell functions including proliferation, differentiation and apoptosis. In recent years its involvement in bone homeostasis has attracted a significant consideration. We hypothesized that Notch signaling pathway, which has a complex interplay with proinflammatory cytokines and bone resorption regulators, contributes to alveolar bone resorption via increased Notch receptors on immune cell surface and stimulates Notch receptor intracellular domain (NICD) translocation into the nucleus. The potential benefit of medications aimed to down-regulate these pathways in apical periodontitis treatment remains to be assessed.

Notch Signaling Pathway in Apical Periodontitis: Correlation with Bone Resorption Regulators and Proinflammatory Cytokines.

INTRODUCTION: The exact mechanisms of periapical bone resorption have not been fully elucidated. This study aimed to analyze the expression of Notch signaling molecules (Notch2, Jagged1, and Hey1) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1ß, and IL-6) in human apical periodontitis lesions with different receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios and determine their potential correlation. METHODS: The study group consisted of 50 periapical lesions collected in conjunction with apicoectomy. The relative gene expression of the investigated molecules (Notch2, Jagged1, Hey1, RANKL, OPG, TNF-α, IL-1ß, and IL-6) in all tissue samples was analyzed using reverse transcriptase real-time polymerase chain reaction. The Student t test, Mann-Whitney U test, and Spearman correlation were used for statistical analysis. RESULTS: Based on the RANKL/OPG ratio, periapical lesions were either RANKL predominant (RANKL > OPG, n = 33) or OPG predominant (RANKL < OPG, n = 17). Symptomatic lesions occurred more frequently in RANKL-predominant compared with OPG-predominant lesions (24 vs 7, P = .029). Notch2, Jagged1, Hey1, and TNF-α were significantly overexpressed in lesions with predominant RANKL compared with lesions with predominant OPG (P = .001, P = .001, P = .027, and P = .016, respectively). Significant correlations were observed between the investigated genes in periapical lesions. CONCLUSIONS: Notch signaling appeared to be activated in periapical inflammation. An increase in Notch2, Jagged1, Hey1, and TNF-α expression in RANKL-predominant periapical lesions corroborates their joined involvement in extensive periapical bone resorption.

Epstein-Barr virus infection induces bone resorption in apical periodontitis via increased production of reactive oxygen species.

Chronic inflammatory processes in periapical tissues caused by etiological agents of endodontic origin lead to apical periodontitis. Apart from bacteria, two herpesviruses, Epstein-Barr virus (EBV) and Human cytomegalovirus (HCMV) are recognized as putative pathogens in apical periodontitis. Although previous reports suggest the involvement of EBV in the pathogenesis of apical periodontitis, its exact role in periapical bone resorption has not yet been fully elucidated. We hypothesize that EBV infection in apical periodontitis is capable of inducing periapical bone resorption via stimulation of reactive oxygen species (ROS) overproduction. Increased levels of ROS induce expression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL). RANKL binding to receptor activator of nuclear factor κB (RANK) present on the surface of preosteoclasts induces their maturation and activation which consequently leads to bone resorption. The potential benefit of antiviral and antioxidant-based therapies in periapical bone resorption treatment remains to be assessed.