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GFP-positive odontogenic cells sequentially decreased in JE. (A) Schema of the GFP-positive tooth germ transplantation method (top). Histological analysis of periodontal tissue around the erupted GFPpositive transplanted teeth in WT mice on day 50, 80, 110, 140, and 200 after transplantation (bottom). (B) Representative bright-(left) and dark-field (right) imaging of an erupted GFP-positive tooth in a WT mouse on day 50 after transplantation. Scale bars represent 500 μm. (C) Representative micro-3DCT image of the erupted GFP-positive tooth on day 50 after transplantation (white arrowhead). (D) Representative fluorescence image of the transverse section of periodontal tissue around the erupted GFP-positive tooth in the WT mouse on day 50 after transplantation. Scale bar represents 200 μm. Abbreviations: OGE, oral gingival epithelium; JE, junctional epithelium; DP, dental pulp; PL, periodontal ligament. (E) Hematoxylin and eosin (H&E) stained (upper row) and fluorescence images (lower row) of transverse sections of periodontal tissue around the erupted GFPpositive teeth in the WT mice on day 50, 80, 110, 140, and 200 after transplantation. From day 110 to 140, GFP-positive cells gradually decreased. On day 200, almost all JE cells were GFP-negative. Dotted lines show the basement membrane. Representative images were taken from three independent mouse samples (n = 3). Scale bars represent 100 μm. Abbreviations: OGE, oral gingival epithelium; JE, junctional epithelium; DP, dental pulp.
Source publication
Junctional epithelium (JE), which is derived from odontogenic epithelial cells immediately after eruption, is believed to be gradually replaced by oral gingival epithelium (OGE) over a lifetime. However, the detailed process of replacement remains unclear. The aim of the present study was to clarify the process of JE replacement by OGE cells using...
Citations
... While ERM has been reported to be involved in enamel, cementum and PDL regeneration following tooth injury and inflammation, JE is ascribed an important role in attaching the oral gingival epithelium to the tooth surface as well as in providing protection to the constant microbial challenge from the oral cavity (Hamamoto et al., 1996;Davis, 2018;Hermans et al., 2021;Fischer and Aparicio, 2022). Whereas the ERM developmentally results from disintegration of Hertwig's epithelial root sheath (HERS), JE is considered to develop upon tooth eruption from the reduced enamel epithelium (REE), the layer of mAB and OEE covering the developed enamel before eruption (Supplementary Figure S4C) (Luan et al., 2006;Kato et al., 2019). Our observation that perio-ERM displays an intermediate transcriptional and regulatory profile between DF-ERM and JE may indicate that the developmental origins of ERM and JE are not as distinct as previously thought, and advances the possibility that HERSderived ERM contributes to JE formation and/or REE to ERM development (and then further to JE) (Supplementary Figure S4C), both not excluded by current knowledge. ...
Single-cell (sc) omics has become a powerful tool to unravel a tissue’s cell landscape across health and disease. In recent years, sc transcriptomic interrogation has been applied to a variety of tooth tissues of both human and mouse, which has considerably advanced our fundamental understanding of tooth biology. Now, an overarching and integrated bird’s-view of the human and mouse tooth sc transcriptomic landscape would be a powerful multi-faceted tool for dental research, enabling further decipherment of tooth biology and development through constantly progressing state-of-the-art bioinformatic methods as well as the exploration of novel hypothesis-driven research. To this aim, we re-assessed and integrated recently published scRNA-sequencing datasets of different dental tissue types (healthy and diseased) from human and mouse to establish inclusive tooth sc atlases, and applied the consolidated data map to explore its power. For mouse tooth, we identified novel candidate transcriptional regulators of the ameloblast lineage. Regarding human tooth, we provide support for a developmental connection, not advanced before, between specific epithelial compartments. Taken together, we established inclusive mouse and human tooth sc atlases as powerful tools to potentiate innovative research into tooth biology, development and disease. The maps are provided online in an accessible format for interactive exploration.
... We showed that the JE and the OGE were derived from different stem cells, and we successfully visualized their borders. In our previous studies, the JE cells in transplanted tooth germs were replaced by the OGE cells from the basal cell layer over time, and all the JE cells were replaced by the OGE cells 90-150 d after tooth eruption 18 . Previous studies have attempted to verify the process by which the JE derived from odontogenic epithelium replaces cells derived from the OGE. ...
The junctional epithelium (JE) is an epithelial component that attaches directly to the tooth surface and performs the unique function of protecting against bacterial infections; its destruction causes inflammation of the periodontal tissue and loss of alveolar bone. A recent study that used the single-color lineage tracing method reported that JE is maintained by its stem cells. However, the process by which individual stem cells form the entire JE around a whole tooth remains unclear. Using a 4-color lineage tracing method, we performed a detailed examination of the dynamics of individual stem cells that constitute the entire JE. The multicolor lineage tracing method showed that single-color areas, which were derived from each cell color, replaced all the constituent JE cells 168 d after the administration of tamoxifen. The horizontal section of the first molar showed that the single-color areas in the JE expanded widely. We detected putative stem cells at the external basal layer farthest from the enamel. In this study, JE cells that were supplied from different stem cells were visualized as individual monochromatic regions, and the JE around the first molar was maintained by several JE-specific stem cells. These findings indicated that the JE consisted of several cell populations that were supplied from their multiple stem cells and could help to explore the mechanisms involved in periodontal tissue homeostasis.
... The histological changes caused by uremia are similar to those caused by other forms of periodontal disease, including replacement of specialized junctional epithelium [19] with proliferating epithelium with deep sulcal folds, which appears similar to the pocket epithelium seen in humans with periodontal disease [20]. We also demonstrated aberrant bone formation in the alveolar bone crest adjacent to in amed periodontal structures. ...
It is presently unclear why there is a high prevalence of periodontal disease (PD) in individuals living with chronic kidney disease (CKD). By employing three different models in rats and mice, we demonstrate that experimental uremia causes periodontal bone loss. Uremia alters the biochemical composition of saliva and induces progressive dysbiosis of the oral microbiota, with microbial samples from uremic animals displaying reduced overall bacterial growth, increased alpha diversity, reduced abundance of key components of the healthy oral microbiota such as Streptococcus and Rothia, and an increase in minor taxa including those from gram-negative phyla Proteobacteria and Bacteroidetes. We show that transfer of oral microbiota from uremic mice induces PD in germ-free animals, whilst co-housing with healthy animals ameliorates the PD phenotype in rats. Thus, we advocate that periodontal disease should be regarded as a bacterially mediated complication of chronic uremia.
... It is generally thought that the JE is gradually replaced by cells from the OE (Yajima-Himuro et al., 2014) and that following its surgical removal, the JE can rapidly reform from the OE (Kato et al., 2019;Listgarten, 1967Listgarten, , 1972Masaoka et al., 2009;Wazen et al., 2015). ...
... The historical literature states that the JE can regenerate, and more recent studies suggest that it does so via contributions from the adjacent OE (Kato et al., 2019;Nakamura, 2018). The OE and JE, however, are histologically distinct since the former is keratinized and the latter is not (Figure 3(a)). ...
... Is the JE a separate entity, or is it an adaptation of the OE? Recent data argue that it is an adaptation because the OE eventually contributes cells to the JE (Kato et al., 2019). Our data support the first part of this model, in which the JE and its Wnt-responsive status are established at its origin from the REE (Figure 1). ...
Aim:
To identify the molecular mechanisms mediating the persistent defensive functions of the self-renewing junctional epithelium (JE).
Materials and methods:
Two strains of Wnt reporter mice, Axin2CreErt2/+ ;R26RmTmG/+ and Axin2LacZ/+ , were employed, along with three clinically relevant, experimental scenarios where the function of the JE is disrupted: after tooth extraction, after a partial gingivectomy and after a complete circumferential gingivectomy.
Results:
Using transgenic Wnt reporter strains of mice, we established the JE is a Wnt-responsive epithelium beginning at the time of its formation, and that it maintains this status into adulthood. After tooth extraction, progeny of the initial Wnt-responsive JE population directly contributed to healing, and ultimately adopted an oral epithelium (OE) phenotype. In the traditional partial gingivectomy model, the JE completely regenerated and did so via progeny of the original Wnt-responsive population. However, following circumferential gingivectomy, the OE was incapable of reestablishing a functional JE.
Conclusions:
A Wnt-responsive niche at the interface between tooth and oral epithelia is required for a functional JE.
The extracellular matrix (ECM) is a complex non-cellular three-dimensional macromolecular network present within all tissues and organs, forming the foundation on which cells sit, and composed of proteins (such as collagen), glycosaminoglycans, proteoglycans, minerals, and water. The ECM provides a fundamental framework for the cellular constituents of tissue and biochemical support to surrounding cells. The ECM is a highly dynamic structure that is constantly being remodeled. Matrix metalloproteinases (MMPs) are among the most important proteolytic enzymes of the ECM and are capable of degrading all ECM molecules. MMPs play a relevant role in physiological as well as pathological processes; MMPs participate in embryogenesis, morphogenesis, wound healing, and tissue remodeling, and therefore, their impaired activity may result in several problems. MMP activity is also associated with chronic inflammation, tissue breakdown, fibrosis, and cancer invasion and metastasis. The periodontium is a unique anatomical site, composed of a variety of connective tissues, created by the ECM. During periodontitis, a chronic inflammation affecting the periodontium, increased presence and activity of MMPs is observed, resulting in irreversible losses of periodontal tissues. MMP expression and activity may be controlled in various ways, one of which is the inhibition of their activity by an endogenous group of tissue inhibitors of metalloproteinases (TIMPs), as well as reversion-inducing cysteine-rich protein with Kazal motifs (RECK).
Organoid models provide powerful tools to study tissue biology and development in a dish. Presently, organoids have not yet been developed from mouse tooth. Here, we established tooth organoids (TOs) from early-postnatal mouse molar and incisor, which are long-term expandable, express dental epithelium stem cell (DESC) markers, and recapitulate key properties of the dental epithelium in a tooth-type-specific manner. TOs display in vitro differentiation capacity toward ameloblast-resembling cells, even more pronounced in assembloids in which dental mesenchymal (pulp) stem cells are combined with the organoid DESCs. Single-cell transcriptomics supports this developmental potential and reveals co-differentiation into junctional epithelium-and odontoblast-/cementoblast-like cells in the assembloids. Finally, TOs survive and show ameloblast-resembling differentiation also in vivo. The developed organoid models provide new tools to study mouse tooth-type-specific biology and development and gain deeper molecular and functional insights that may eventually help to achieve future human biological tooth repair and replacement.
