New Insights Into Tooth Formation and Regenerative Potential

Authors propose a model where dental cell position along the lingual-buccal axis guides tooth formation via WNT/BMP signals.

Tooth development is a highly dynamic process, progressing through distinct stages: the bud, the cap, and the bell, followed by root formation and the emergence of a fully formed tooth. Critical transitions, such as the shift from bud to cap, are driven by complex interactions between epithelial and mesenchymal cells ().

Moreover, the ultimate fate of each cell in a developing tooth is influenced by its position within the embryo, as varying concentrations of signaling molecules and growth factors provide spatial cues that guide differentiation.

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From Bud to Bell: The Established Stages of Tooth Development

For decades, scientists have understood that a single tooth begins as a small bud of outer epithelial cells, which invades deeper mesenchymal tissue. This bud then curves to form a cap shape and folds further into the bell stage, eventually giving rise to the mature structure of the tooth, complete with surrounding bone and gums.

Building on this foundation, Dr. Han-Sung Jung and his team at the Yonsei University College of Dentistry in Korea investigated how the spatial position of young epithelial and mesenchymal dental cells affects their developmental trajectory. Their findings, recently published in the International Journal of Oral Science, shed new light on the intricate mechanisms that govern tooth formation and could have implications for dental tissue engineering and regenerative therapies.

Lead author Dr. Jung said that his team “performed this study to identify how positional identity along the lingual-buccal axis determines distinct developmental fates of dental mesenchyme. This research has the potential to significantly impact our understanding of tooth development,” he says.

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The investigators separated the mesenchymal cells on the lingual and buccal sides at both cap and bell stages of a developing mouse embryo and - compared their gene expression profiles through RNA-seq followed by Gene Ontology enrichment analysis to understand the differences with position and time.

They then transplanted the cap-stage lingual and buccal cells separately under the kidney capsule of immunocompromised mice to see what each grew into. Analysis showed that cells on the lingual side were mainly geared toward making the tooth itself and shaping its structure, while cells on the buccal side were more focused on stem cell activity, forming surrounding tissues, and supporting tooth growth and repair. Not surprisingly, only the lingual cells in the mouse kidney grew into tooth enamel.

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The researchers also reported haphazardly mixing up cap-stage, tagged buccal and lingual cells of genetically engineered mice. “We were curious to know if they could find their original place and reorganize when the fluorescently labeled lingual and buccal mesenchymal cells were mixed randomly, which they not only did, but the lingual cells grew into dentin to form the tooth as before. This phenomenon is called cellular self-organization,” says first author Eun-Jung Kim.

Furthermore, they have extensively studied the signaling molecules in each group and found that WNT signalling and R-spondins (Rspo1/2/4) are enriched in lingual cells, along with high proliferation, low cell death, and higher migration rate, aiding tooth formation. On the other hand, buccal cells show increased expression of BMP inhibitors, lower proliferation, higher apoptosis, and slower migration, favoring bone and surrounding tissue formation.

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WNT/BMP Signaling Determines Dental Cell Fate Along the Lingual-Buccal Axis

In conclusion, the authors proposed a model of dental cell positioning based on the lingual-buccal axis for tooth and surrounding tissue formation. The characteristics of dental mesenchymal cells were found to vary along this axis, and the fate of the tooth and surrounding tissue formation is determined by mesenchymal cells via WNT/BMP signaling.

Deeper knowledge of the molecular nuances of tooth development will inspire further research in tissue engineering and regenerative medicine, which may ultimately lead to advancements in stem cell-based tooth regeneration and more effective therapeutic applications for dental restoration and repair.

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