The temporomandibular joint (TMJ) is one of the most used joints in the body. Defects and wear in the cartilage of the joint, condyle, and fibrocartilage disc lie at the heart of many common TMJ disorders. During postnatal development, the condyle acts as a growth center for the mandible, with cells moving as a conveyor belt away from the top of the condyle as they differentiate. The superficial layers of the condyle have been proposed to contain stem/progenitor populations to allow growth and maintain homeostasis. Here we have focused on the role of fibroblast-specific protein 1 (FSP1; also known as S100a4) as a key fibroblast stem/progenitor marker for the condyle. Lineage tracing with FSP1-Cre;R26RmTmG mice revealed that FSP1-expressing cells were restricted to the superficial fibroblast zone, giving rise to all layers of the condyle over time. The FSP1-expressing cells overlapped with other putative stem cell markers of the condyle, such as Gli1 and scleraxis. BrdU pulse chase experiments highlighted that a subset of FSP1 fibrocartilage was label retaining, suggesting that FSP1 labels a novel stem/progenitor cell population in the condyle. Destruction of FSP1-expressing cells by conditional diphtheria toxin activity in FSP1-Cre;R26RDTA mice resulted in severe TMJ osteoarthritis with loss of the cartilage structure. Lgr5-expressing cells in the superficial layer of the condyle have been shown to create a Wnt inhibitory niche. FSP1 expression postnatally was associated with a reduction in canonical Wnt activity in the condyle. Importantly, constitutive activation of Wnt/β catenin in FSP1-expressing cells led to a downregulation of FSP1 and progressive postnatal loss of TMJ condylar hyaline cartilage due to loss of the superficial stem/progenitor cells. These data demonstrate a novel role for FSP1-expressing cells in the superficial zone in growth and maintenance of the TMJ condylar cartilage and highlight the importance of regulating Wnt activity in this population.

• Keywords
• Wnt signaling, condyle, fibrocartilage, osteoarthritis, stem cell, temporomandibular disorders,
• MeSH
• Fibroblasts metabolism   MeSH
• Homeostasis physiology   MeSH
• Stem Cells * metabolism   physiology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Mandibular Condyle growth & development   cytology   metabolism   MeSH
• S100 Calcium-Binding Protein A4 * metabolism   physiology   MeSH
• Temporomandibular Joint * growth & development   cytology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Lgr5 protein, mouse MeSH Browser
• Receptors, G-Protein-Coupled MeSH
• S100 Calcium-Binding Protein A4 * MeSH
• S100a4 protein, mouse MeSH Browser

Recent years have improved our understanding of the plasticity of cell types behind inducing, building, and maintaining different types of teeth. The latest efforts were aided by progress in single-cell transcriptomics, which helped to define not only cell states with mathematical precision but also transitions between them. This includes new aspects of dental epithelial and mesenchymal stem cell niches and beyond. These recent efforts revealed continuous and fluid trajectories connecting cell states during dental development and exposed the natural plasticity of tooth-building progenitors. Such "developmental" plasticity seems to be employed for organizing stem cell niches in adult continuously growing teeth. Furthermore, transitions between mature cell types elicited by trauma might represent a replay of embryonic continuous cell states. Alternatively, they could constitute transitions that evolved de novo, not known from the developmental paradigm. In this review, we discuss and exemplify how dental cell types exhibit plasticity during dynamic processes such as development, self-renewal, repair, and dental replacement. Hypothetically, minor plasticity of cell phenotypes and greater plasticity of transitions between cell subtypes might provide a better response to lifetime challenges, such as damage or dental loss. This plasticity might be additionally harnessed by the evolutionary process during the elaboration of dental cell subtypes in different animal lineages. In turn, the diversification of cell subtypes building teeth brings a diversity of their shape, structural properties, and functions.

• Keywords
• cell differentiation, dental informatics/bioinformatics, developmental biology, single-cell RNA-seq, stem cell(s), tooth development,
• MeSH
• Regeneration physiology   MeSH
• Tooth * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Frizzled 6 (FZD6) belongs to a family of proteins that serve as receptors in the WNT signaling pathway. FZD6 plays an important role in the establishment of planar cell polarity in many embryonic processes such as convergent extension during gastrulation, neural tube closure, or hair patterning. Based on its role during hair development, we hypothesized that FZD6 may have similar expression pattern and function in the dental lamina, which is also a distinct epithelial protrusion growing characteristically angled into the mesenchyme. Diphyodont minipig was selected as a model species because its dentition closely resemble human ones with successional generation of teeth initiated from the dental lamina. We revealed asymmetrical expression of FZD6 in the dental lamina of early as well as late stages during its regression with stronger expression located on the labial side of the dental lamina. During lamina regression, FZD6-positive cells were found in its superficial part and the signal coincided with the upregulation of molecules involved in epithelial-mesenchymal transition and increased migratory potential of epithelial cells. FZD6-expression was also turned on during differentiation of cells producing hard tissues, in which mature odontoblasts, ameloblasts, or surrounding osteoblasts were FZD6-positive. On the other hand, the tip of successional lamina and its lingual part, in which progenitor cells are located, exhibited FZD6-negativity. In conclusion, asymmetrical expression of FZD6 correlates with the growth directionality and side-specific morphological differences in the dental lamina of diphyodont species. Based on observed expression pattern, we propose that the dental lamina is other epithelial tissue, where planar cell polarity signaling is involved during its asymmetrical growth.

• Keywords
• FZD6, WNT signaling, ameloblast, epithelial remnants, odontoblast, osteoblast, planar cell polarity (PCP), successional dental lamina,
• Publication type
• Journal Article MeSH

The successional dental lamina (SDL) plays an essential role in the development of replacement teeth in diphyodont and polyphyodont animals. A morphologically similar structure, the rudimental successional dental lamina (RSDL), has been described in monophyodont (only one tooth generation) lizards on the lingual side of the developing functional tooth. This rudimentary lamina regresses, which has been proposed to play a role in preventing the formation of future generations of teeth. A similar rudimentary lingual structure has been reported associated with the first molar in the monophyodont mouse, and we show that this structure is common to all murine molars. Intriguingly, a lingual lamina is also observed on the non-replacing molars of other diphyodont mammals (pig and hedgehog), initially appearing very similar to the successional dental lamina on the replacing teeth. We have analyzed the morphological as well as ultrastructural changes that occur during the development and loss of this molar lamina in the mouse, from its initiation at late embryonic stages to its disappearance at postnatal stages. We show that loss appears to be driven by a reduction in cell proliferation, down-regulation of the progenitor marker Sox2, with only a small number of cells undergoing programmed cell death. The lingual lamina was associated with the dental stalk, a short epithelial connection between the tooth germ and the oral epithelium. The dental stalk remained in contact with the oral epithelium throughout tooth development up to eruption when connective tissue and numerous capillaries progressively invaded the dental stalk. The buccal side of the dental stalk underwent keratinisation and became part of the gingival epithelium, while most of the lingual cells underwent programmed cell death and the tissue directly above the erupting tooth was shed into the oral cavity.

• MeSH
• Apoptosis physiology   MeSH
• Embryo, Mammalian embryology   MeSH
• Hedgehogs MeSH
• Molar embryology   MeSH
• Mice MeSH
• Swine MeSH
• SOXB1 Transcription Factors metabolism   MeSH
• Mouth Mucosa embryology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Sox2 protein, mouse MeSH Browser
• SOXB1 Transcription Factors MeSH