Journal of dental research最新文献

{"title":"Nociceptor Neurons Facilitate Orthodontic Tooth Movement via Piezo2 in Mice.","authors":"S Wang, X Nie, G Parastooei, S Kumari, Y Abbasi, O Elnabawi, E-K Pae, C C Ko, M-K Chung","doi":"10.1177/00220345251317429","DOIUrl":"10.1177/00220345251317429","url":null,"abstract":"<p><p>Multiple sensory afferents, including mechanosensitive and nociceptive nerves, are projected to the periodontium. Peptidergic afferents expressing transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin, mediate pain caused by orthodontic forces. However, their role in orthodontic force-induced alveolar bone remodeling is poorly understood as is the contribution of mechanosensitive ion channels such as Piezo2 in nociceptive nerves. To investigate this role, we studied orthodontic tooth movement and alveolar bone remodeling using neural manipulations and genetic mouse models. Chemical ablation of TRPV1-expressing afferents localized to the trigeminal ganglia decreased orthodontic force-induced tooth movement and the number of osteoclasts in alveolar bone on the compression side. The extent of the force-induced increase in the ratio of receptor activator of nuclear factor kappa-B ligand/osteoprotegerin in the periodontium was modestly decreased in the chemical ablation group. Furthermore, chemogenetic silencing of TRPV1-lineage afferents reduced orthodontic tooth movement and the number of osteoclasts. Piezo2 was expressed in most periodontal afferents, and chemogenetic inhibition of Piezo2-expressing neurons decreased orthodontic tooth movement and the number of osteoclasts. In addition, the conditional knockout of Piezo2 in TRPV1-lineage afferents decreased orthodontic tooth movement and the number of osteoclasts. Overall, these results suggest that nociceptor neurons play critical roles in orthodontic force-induced alveolar bone remodeling and that the mechanical activation of neuronal Piezo2 in nociceptive nerves facilitates orthodontic tooth movement and associated alveolar bone remodeling.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"890-899"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecules Targeting EriC^F1 Increase <i>Streptococcus mutans</i> Fluoride Sensitivity.","authors":"Q Weng, J Liu, S Yao, Q Ma, T Gong, Y Lin, Y Li, Y Zhang","doi":"10.1177/00220345251318688","DOIUrl":"10.1177/00220345251318688","url":null,"abstract":"<p><p>Dental caries, as one of the prevalent oral infectious diseases worldwide, constitutes a considerable disease burden. Fluoride has been widely used to prevent dental caries for decades. However, fluoride alone may not always be sufficient. The major cariogenic bacterial species, <i>Streptococcus mutans</i>, has not been effectively controlled by daily fluoride exposure, possibly because it has a detoxification mechanism. Studies have shown that most microorganisms have fluoride exporters dedicated to exporting fluoride ions (F^-). <i>S. mutans</i> possesses 2 homologous genes, <i>eriC^F1</i> and <i>eriC^F2</i>, which encode fluoride exporters, but their function has not been fully clarified. In this work, we constructed the markerless gene deletion mutants, overexpression, and complemented strains of <i>S. mutans</i> UA159. Assessing fluoride sensitivity, intracellular F^- levels, and cell membrane permeability revealed that EriC^F1 was the major functional unit of the fluoride exporter in <i>S. mutans</i>. To further enhance the antibacterial efficiency of fluoride, we identified 3 diphenylurea derivatives that might target EriC^F1 by molecular docking, which significantly enhanced the antibacterial effect of sodium fluoride (NaF) by synergistically impeding fluoride efflux, as demonstrated by chequerboard broth microdilution assays. Moreover, these compounds combined with 1 mM NaF impaired the cariogenicity of <i>S. mutans</i> significantly in vivo and with good biocompatibility, especially compounds 9 and 15. Collectively, these findings suggest that fluoride exporters in <i>S. mutans</i> could serve as a potential target for caries prevention, and the diphenylurea derivatives identified for targeting EriC^F1 could be a valuable therapeutic approach when combined with fluoride, providing promising measures for dental caries prevention.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"900-909"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TTP as Tumor Suppressor and Inflammatory Regulator in Oral Carcinogenesis.","authors":"D M Ferri, M Ayre, L Ariza Bareño, M Stedile, A V DiGaudio, G Fernandez Ugazio, E C Kordon, P J Blackshear, A Urtreger, A R Raimondi","doi":"10.1177/00220345251316828","DOIUrl":"10.1177/00220345251316828","url":null,"abstract":"<p><p>The stability of messenger RNA (mRNA) is controlled by proteins that bind to adenosine-uridine-rich sequences (AREs) in their 3' untranslated regions (3'UTR), known as AU-binding proteins. One of these proteins is tristetraprolin (TTP; encoded by <i>Zfp36</i>), which promotes degradation of mRNAs with AREs in their 3'UTR. TTP accelerates the decay of its target transcripts, many of which encode proinflammatory mediators that promote tumorigenesis. TTP underexpression has been reported in multiple cancer types. Oral squamous cell carcinoma is an aggressive disease characterized by high morbidity and few therapeutic options. The role of TTP has not been studied in oral epithelium homeostasis nor in its carcinogenesis. Herein, using tissue-specific TTP knockout mice (TTP-KO), we show that TTP expression is relevant for oral epithelium homeostasis. TTP-KO mice developed dysplastic lesions in the tongue along with inflammatory infiltrates in the connective tissue. Analysis of the inflammatory infiltrate revealed the presence of mast cells (MCs), CD45+ cells, and CD11b+ cells, with the MCs being the most abundant cell type and associated with cyclooxygenase-2 expression. Recruitment of MCs was dependent on tumor necrosis factor-α (TNFα) upon TTP ablation in the tongue. Although the infiltration of MCs was dependent on TNFα activity, this did not affect the development of tongue dysplasia. We analyzed the status of the NF-κB pathway, finding its activation. In addition, we demonstrate that K-ras activation combined with <i>Zfp36</i> deletion leads to the rapid onset of the oral tongue phenotype and significantly reduces mouse survival. Our results support the notion that TTP expression protects against oral carcinogenesis, regulates the inflammatory infiltrate, and maintains the epithelial microenvironment, potentially serving as a barrier to tumorigenesis.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"795-805"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Birth Cohort Study Identifies <i>Candida albicans</i> as a Risk Factor for Dental Caries.","authors":"N Alkhars, S Manning, N Al Jallad, Y Zeng, T T Wu, C Fogarty, M Mendoza, E van Wijngaarden, D T Kopycka-Kedzierawski, R Billings, K Fiscella, H Koo, J Xiao","doi":"10.1177/00220345251340040","DOIUrl":"https://doi.org/10.1177/00220345251340040","url":null,"abstract":"<p><p><i>Candida albicans</i> has been implicated as a potential cariogenic microorganism, yet no prospective longitudinal studies have examined its role in severe early childhood caries (S-ECC). This study aimed to evaluate the association between oral <i>C. albicans</i> and the onset of S-ECC in a longitudinal setting. This prospective birth cohort study (2018 to 2023) enrolled 186 low-income pregnant women in their third trimester in Western New York, United States. Overall, 160 eligible infants born to these women were followed from birth to 2 y at 7 time points. Oral samples were collected to assess <i>Candida</i> species (<i>C. albicans</i>, <i>Candida krusei</i>, and <i>Candida glabrata</i>) and <i>Streptococcus mutans</i>. The primary outcome was the onset of S-ECC. Two-step LASSO (least absolute shrinkage and selection operator)-penalized logistic regression models were developed to identify predictive factors for S-ECC from 234 covariates grouped by their proximal association with S-ECC: infant oral microorganisms, biological-environmental factors, and maternal characteristics. Logistic regression was used to validate the association between <i>C. albicans</i> and S-ECC. Among the 118 children who completed the study, 28% developed S-ECC. The racial background of the cohort was 57% Black, 21% White, and 22% other. Oral <i>C. albicans</i> colonized in 12% of infants at 1 wk, peaking at 57% by 18 mo. Salivary <i>C. albicans</i> was associated with a 4.47-fold increased risk for S-ECC (odds ratio [OR]; 95% CI, 1.28 to 15.58; <i>P</i> = 0.02), in addition to other risk factors, including plaque score (OR, 5.19; 95% CI, 2.10 to 12.83) and salivary <i>S. mutans</i> (OR, 9.74; 95% CI, 2.27 to 41.79). <i>C. albicans</i> demonstrated strong time sensitivity in predicting S-ECC as early as 1 mo, contrasting with <i>S. mutans</i>, which exhibited predictive ability after 1 y. Oral <i>C. albicans</i> could serve as a novel biological marker for predicting ECC risk in infancy, shining a light on opportunities to develop innovative caries-predictive and preventive strategies targeting fungal contributions in pediatric care settings.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251340040"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Insights into Unicystic and Solid Ameloblastoma Heterogeneity.","authors":"C Feng, X Dou, S-R Li, X Xu, Z Dang, Z Jiang, E Jiang, Z Shang","doi":"10.1177/00220345251340892","DOIUrl":"https://doi.org/10.1177/00220345251340892","url":null,"abstract":"<p><p>The clinical classification of ameloblastoma (AM) plays a decisive role in the selection of treatment options, but the difference of single-cell landscape among clinical classifications is still unclear. At the same time, there is an urgent need to understand the key cell subtypes that determine the clinical subtypes. We characterized the single-cell transcriptional profiles of clinical subtypes of AM. We also characterized a pseudotime transition trajectory from immunoactive epithelial cells to vascular-associated fibroblasts, identifying key transcription factors involved in this process. Notably, we observed significant heterogeneity between M1 and M2 macrophages among the clinical subtypes of AM. Furthermore, our analysis revealed that metabolic disorder in AM was primarily driven by the metabolic disturbances in M1 and M2 macrophages. At the cellular communication level, we highlighted the role of M2 macrophages in mediating cell interactions, focusing on the RANKL/RANK pathway associated with osteoclast activity. Finally, we attempted to establish a unicystic AM-derived epithelial cell line and utilized it to construct an AM-like organoid model; we found that M2 macrophages competed with AM for L-cysteine to achieve cystic changes in the solid lesion. Our exploration of pathogenesis underlying various clinical types of AM advances our knowledge of AM heterogeneity, offering promising targets for novel therapeutic strategies.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251340892"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Release of Bisphenol A from Dental Materials: Risks and Future Perspectives.","authors":"A Tichy, T Srolerova, F Schwendicke","doi":"10.1177/00220345251337728","DOIUrl":"https://doi.org/10.1177/00220345251337728","url":null,"abstract":"<p><p>The gradual phaseout of dental amalgam has contributed to a significant increase in the use of resin-based materials. While these materials offer several desirable properties, concerns persist regarding their biocompatibility, particularly the release of bisphenol A (BPA). BPA is an endocrine-disrupting chemical linked to adverse effects on human health, including reproductive, developmental, and metabolic disorders. Although food contact materials are the primary source of human BPA exposure and the contribution of dental materials is minor, the associated risks cannot be dismissed due to BPA's nonmonotonic dose-response relationship. In 2023, the European Food Safety Authority proposed a 20,000-fold reduction in the tolerable daily intake of BPA to 0.2 ng/kg body weight, citing immune system effects at extremely low doses. This proposal has sparked regulatory and scientific debate, as adopting such a stringent limit would effectively ban the use of BPA in food contact materials and many other products. Given this context, it is essential to assess the release of BPA from dental materials both in vitro and in vivo. However, data interpretation is complicated by methodological inconsistencies, including variations in material composition, specimen preparation, choice of extraction media, experimental duration, and analytical methods. In addition, pivotal differences in reporting results make it difficult to synthesize findings and draw reliable conclusions. This review examines the controversy surrounding BPA, critically evaluates evidence on its release from dental materials, and explores mitigation strategies. By highlighting gaps in knowledge and proposing future research directions, this review aims to provide clinicians, researchers, and policymakers with a clearer understanding of BPA-related complexities, ultimately contributing to patient safety and material innovation.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251337728"},"PeriodicalIF":0.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perineural Invasion Exhibits Traits of Neurodegeneration.","authors":"M Zhang, M Yuan, K Asam, Z Gong, T Xie, F Gleber-Netto, M D Santi, Y Kobayashi, E Shimizu, B Aouizerat, M Amit, M D Boada, Y Ye","doi":"10.1177/00220345251334379","DOIUrl":"https://doi.org/10.1177/00220345251334379","url":null,"abstract":"<p><p>Perineural invasion (PNI) frequently occurs in head and neck squamous cell carcinoma (HNSCC), which correlates with poor survival and induces intractable pain and numbness. There is no effective treatment for PNI or associated pain. To gain a better understanding of PNI at the molecular and cellular level, we produced an orthotopic, syngeneic mouse model of PNI by inoculating mouse oral cancer cells into the infraorbital nerve (ION), a nerve that is susceptible to cancer invasion in patients with HNSCC. Mice with PNI in the ION exhibited both evoked and spontaneous nociception and impaired oral function, mimicking human conditions. PNI resulted in a drastic reduction in the proportion and altered mechanical thresholds in mechanically sensitive trigeminal neurons; axon and myelin abnormalities, as well as phagocytic cells, were observed. The tumor bed is marked by CD4⁺ and CD8⁺ T cells, CD68⁺ cells, and F4/80⁺ macrophages, while CD4⁺, CD8⁺, and CD68⁺ immune cells can be found surrounding the nerve. The intraneural niche is predominantly marked by CD68 that does not overlap with F4/80 but instead overlaps with NF200 and MPZ and occasionally with DAPI, suggesting these are likely phagocytic macrophages or Schwann cells. Finally, our RNA sequencing pathway analysis in mouse and human HNSCC found perturbed pathways in neuroinflammation, mitochondrial dysfunction, and cellular metabolism. Additionally, ION-PNI exhibits nerve degenerative features with perturbed pathways that are observed in Alzheimer, Parkinson, and prion diseases. In conclusion, we report a novel, anatomically relevant in vivo model that could be used to study the cellular and molecular mechanisms of PNI-induced neuropathies. Importantly, we found that PNI resembles neurodegenerative diseases with features of altered sensory transduction and conduction, neuroinflammation, and mitochondrial dysfunction, which may underlie peripheral neuropathies, such as pain.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251334379"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Junctional Epithelium Attachment Is Regulated by Wnt Signaling.","authors":"F Aellos, P L Cuevas, K G Harder, J A Grauer, A Ramos, B Liu, J A Helms","doi":"10.1177/00220345251336168","DOIUrl":"https://doi.org/10.1177/00220345251336168","url":null,"abstract":"<p><p>The molecular mechanisms mediating barrier functions of the junctional epithelium (JE) are incompletely understood. The aim of this study was to gain mechanistic insights into how reduced Wnt/β-catenin signaling affects the metabolism, turnover, and attachment of JE cells to the tooth surface. A membrane-permeable selective inhibitor of the Wntless protein, C59, was topically delivered to the JE. Wnt pathway suppression was verified by using <i>Axin2^LacZ/+</i> and <i>Axin2Cre^ERT2/+;</i><i>R26R^mTmG/+</i> strains of mice. Quantitative analyses were carried out at multiple time points to assess mitotic activity, apoptosis, expression of hemidesmosomal attachment proteins, distribution of immune cells, collagen remodeling, and alveolar bone resorption. To complement these studies, Wntless was genetically deleted in osteocalcin-expressing cells, including those in the JE, after which the same quantitative analyses were performed. C59 caused a dose-dependent inhibition in Wnt signaling, which led to reduced mitotic activity and increased apoptosis in the JE. Continued dosing of C59 was accompanied by downregulation of the hemidesmosome attachment proteins laminin 5, plectin, and integrin β4 and a disruption in collagen orientation. A genetic approach in which Wntless function was inhibited in osteocalcin-expressing JE cells yielded similar inhibitory effects on Wnt signaling, mitotic activity, the JE's attachment to the tooth surface, and an increase in immune cells within the connective tissue. Wnt/β-catenin signaling is required for JE homeostasis, and disruptions to the pathway are sufficient to cause JE breakdown and attachment loss. Methods to modulate Wnt/β-catenin signaling may prove beneficial in restoring JE homeostasis after injury or disease.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251336168"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt1's Differential Effects on Craniofacial Bone and Tooth Development.","authors":"R Mahmoud, A Simon, J Luther, J Pothe, Y Du, C Nottmeier, E Okine, S Knauth, M G Lopez, E Bockamp, J Krivanek, A LeBlanc, J Helms, M Amling, M Kaucka, T Schinke, T Koehne, J Petersen","doi":"10.1177/00220345251336191","DOIUrl":"https://doi.org/10.1177/00220345251336191","url":null,"abstract":"<p><p>The development of craniofacial bones and teeth relies heavily on the Wnt signaling pathway, yet the specific mechanisms and Wnt variants involved remain under continual investigation. Using publicly available single-cell sequencing data from the mouse incisor, we reveal <i>Wnt1</i> expression across dental structures and investigate its role using a <i>Col1a1</i>-dependent <i>Wnt1</i> transgenic mouse model. Inducing <i>Wnt1</i> early on affects craniofacial bone without disturbing tooth development, but prolonged embryonic induction leads to postnatal mortality with osteopetrosis-like bone overgrowth and malformed teeth. While tooth formation was initially unaffected by postnatal <i>Wnt1</i> induction, prolonged activation impaired tooth root formation and odontoblast differentiation, resulting in shortened roots and thinner dentin. Three-dimensional micro-computed tomography quantification reveal that both embryonic and postnatal activation of <i>Wnt1</i> significantly increase neural crest-derived craniofacial bone volume, whereas mesenchymal-derived craniofacial bones are unaffected. Importantly, osteoclastogenesis is suppressed by <i>Wnt1</i> in a dose-dependent manner, revealed through bulk RNA sequencing and in vitro experiments. These findings emphasize the differential effects of <i>Wnt1</i> on bone development based on origin and highlight its role in modulating osteoclast activity, indicating broader implications for craniofacial development and potential therapeutic avenues.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"220345251336191"},"PeriodicalIF":0.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pericytes Are Odontoblast Progenitor Cells Depending on ER Stress.","authors":"T Ouchi, M Ando, R Kurashima, M Kimura, N Saito, A Iwasaki, H Sekiya, K Nakajima, T Hasegawa, T Mizoguchi, Y Shibukawa","doi":"10.1177/00220345241307944","DOIUrl":"10.1177/00220345241307944","url":null,"abstract":"<p><p>Odontoblasts are terminally differentiated cells that exhibit mechanosensitivity and mineralization capacity. Mechanosensitive ion channels such as Piezo1 are present in odontoblasts and are associated with their physiological functions via Ca²⁺ signaling. Both Ca²⁺ signals via Ca²⁺ influx from mechanosensitive ion channels and Ca²⁺ release from Ca²⁺ stores function as secondary messenger systems for various biological phenomena. The endoplasmic reticulum (ER) serves as an intracellular Ca²⁺ store that mobilizes intracellular Ca²⁺. Changes in Ca²⁺ concentration inside the ER are among the factors that cause ER stress. Perivascular cells are located around odontoblasts in the dental pulp. Although such formation indicates that perivascular cells interact with odontoblasts, their detailed profiles under developmental and pathological conditions remain unclear. In this study, we revealed that pericyte marker, neural/glial antigen 2 (NG2)-positive cells, in cell-rich zones (CZs) can differentiate into Piezo1-positive odontoblasts following genetic odontoblast depletion in mice, and modeled as odontoblast death after severe dentin injury and as reparative dentin formation. NG2-positive pericytes differentiated into odontoblasts faster than glial cells. To determine how NG2-positive cells differentiate into Piezo1-positive odontoblasts, we focused on the ER-stress sensor protein, activating transcription factor 6a (ATF6a). After genetic odontoblast depletion, NG2-positive cells regenerated in the odontoblast layer and were capable of acting as functional odontoblasts. In the presence of extracellular Ca²⁺, the application of a sarco/ER Ca²⁺-ATPase (SERCA) inhibitor, thapsigargin, known as an ER-stress inducer, increased the intracellular Ca²⁺ concentration in the odontoblast lineage cells (OLCs). The increase was significantly inhibited by the application of a pharmacologic Piezo1 inhibitor, indicating that ER stress by SERCA inhibition augmented Piezo1-induced responses in odontoblast progenitor cells. However, the physiological activation of G_q-coupled receptors by adenosine diphosphate did not induce Piezo1 activation. Gene silencing of <i>ATF6a</i> and/or <i>NG2</i> impaired the mineralization of OLCs. Overall, ATF6a orchestrates the differentiation of NG2-positive pericytes into functional odontoblasts that act as sensory receptor cells and dentin-forming cells.</p>","PeriodicalId":94075,"journal":{"name":"Journal of dental research","volume":" ","pages":"656-667"},"PeriodicalIF":0.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}