Scientists Discover Stem Cells That Could Regenerate Teeth and Bone

Researchers uncover how cells develop and specialize, advancing prospects for regenerative dental treatments.

Researchers at Science Tokyo have identified two separate stem cell lineages responsible for forming tooth roots and the alveolar bone that anchors teeth in the jaw.

By using genetically modified mice and lineage-tracing methods, the team uncovered how specific signaling pathways direct stem cells to specialize during tooth development. Their findings provide valuable insight that could help advance the field of regenerative dentistry in the future.

The challenge of true tooth regeneration

The ability to regrow lost teeth and their surrounding bone structures remains one of the most sought-after goals in dental science. For many years, tooth replacement has relied on artificial substitutes such as dental implants and dentures. Although these solutions can effectively restore function and appearance, they cannot fully replicate the natural feel, biological integration, or structural complexity of real teeth.

This limitation has motivated researchers to explore how natural tooth formation occurs, in hopes of developing regenerative treatments that could restore lost teeth more completely.

However, tooth and bone formation is an extraordinarily complex process. It depends on the coordinated activity of multiple tissues, including the enamel organ, dental pulp, and jawbone cells. These components must communicate through finely tuned signaling networks to control the formation of the tooth crown, root, and the alveolar bone that supports the tooth. Despite decades of study, many aspects of these interactions remain poorly understood.

Tracing the origins of tooth root and bone cells

To address these knowledge gaps, an international team led by Assistant Professor Mizuki Nagata from the Department of Periodontology at the Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), and Dr. Wanida Ono from the University of Texas Health Science Center at Houston (UTHealth), collaborated with researchers from the University of Michigan and other institutions.

Their work focused on the molecular and cellular mechanisms that guide stem cell differentiation in developing teeth. The results were published as two companion studies in Volume 16 of Nature Communications on July 1 and July 2, 2025.

The team used genetically modified mice and advanced lineage-tracing techniques, investigating how cell populations specialize and organize themselves at the ‘tip’ (apical region) of tooth roots. Through microscopy techniques, fluorescent cellular tags, and gene silencing, the researchers were able to clearly visualize the effects of key signaling proteins on cell fate during tooth development.

Identifying two distinct stem cell populations

In this way, the team identified a previously unrecognized population of mesenchymal stem cells that give rise to two distinct lineages: one strongly associated with tooth root development and the other with alveolar bone formation. The first lineage originates from cells located in the apical papilla within the epithelial root sheath—a cluster of soft tissue at the tip of the growing tooth root.

These cells express CXCL12, a protein that plays a key role in bone formation within bone marrow. Through a chemical signaling pathway known as the canonical Wnt pathway, the apical papilla CXCL12-expressing cells can differentiate not only into tooth-forming odontoblasts, but also into cementum-forming cementoblasts at the elongating tooth root and even alveolar bone-forming osteoblasts under regenerative conditions.

The other lineage is concentrated in the dental follicle, a sac-like structure that envelops the developing tooth and contributes to the formation of the surrounding anchoring. The team found that a population of parathyroid hormone-related protein (PTHrP)-expressing cells can differentiate into cementoblasts, ligament fibroblasts, and alveolar bone-forming osteoblasts. Interestingly, the researchers noted that this transformation only occurs under specific circumstances, as Nagata explains: “We observed that the Hedgehog–Foxf pathway needs to be suppressed to drive the alveolar bone osteoblast fate of PTHrP-expressing cells in the dental follicle, unraveling a unique tooth-specific mechanism of bone formation requiring deliberate on–off regulation of Hedgehog signaling.”

Toward regenerative dental therapies

Together, the findings of these two studies advance our understanding of how teeth and alveolar bone develop in vivo, providing some much-needed clues about their intricate growing mechanisms. “Our findings provide a mechanistic framework for tooth root formation and pave the way for innovative stem-cell-based regenerative therapies for dental pulp, periodontal tissues, and bone,” concludes Nagata, with eyes on the future.

References:

“Wnt-directed CXCL12-expressing apical papilla progenitor cells drive tooth root formation” by Mizuki Nagata, Gaurav T. Gadhvi, Taishi Komori, Yuki Arai, Hiroaki Manabe, Angel Ka Yan Chu, Ramandeep Kaur, Meer Ali, Yuntao Yang, Chiaki Tsutsumi-Arai, Yuta Nakai, Yuki Matsushita, Nicha Tokavanich, W. Jim Zheng, Joshua D. Welch, Noriaki Ono and Wanida Ono, 1 July 2025, Nature Communications.
DOI: 10.1038/s41467-025-61048-x

“A Hedgehog–Foxf axis coordinates dental follicle-derived alveolar bone formation” by Mizuki Nagata, Gaurav T. Gadhvi, Taishi Komori, Yuki Arai, Chiaki Tsutsumi-Arai, Angel Ka Yan Chu, Seth N. Nye, Yuntao Yang, Shion Orikasa, Akira Takahashi, Peter Carlsson, W. Jim Zheng, Joshua D. Welch, Noriaki Ono and Wanida Ono, 2 July 2025, Nature Communications.
DOI: 10.1038/s41467-025-61050-3

Funding: National Institutes of Health, Cancer Prevention and Research Institute of Texas, Japanese Society of Periodontology, Japan Society for the Promotion of Science

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