Abstract
Tooth dentin, secreted by odontoblasts, constitutes most of the tooth structure and provides support and sensory function. However, dentin defects are common and irreparable once they exceed a critical threshold. Human dentin develops from dental papilla (DP) cells under the guidance of the dental epithelium (DE). Here, we present a human tooth development atlas from initiation to erupted stage using single-cell RNA sequencing and spatial transcriptomics, focusing on epithelial-mesenchymal interactions. This atlas reveals that DE orchestrates DP differentiation in a WNT-NOTCH sequential activation model and identifies the key signaling molecules. DLX6-AS1+ DP cells respond to dental epithelial signals and can be isolated from adult dental pulp stem cells (DPSCs). Notably, DLX6-AS1+ DPSCs successfully generate tubular dentin in an in vivo disease model of dentin defects. This research provides valuable information on human tooth development and establishes a basis for repairing regenerative dental tissue.
Data availability
The single-cell RNA sequencing and spatial transcriptomics data for developmental stages 7–8, 9–10, 12, and 15 PCW have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in the National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences, under accession number HRA013557. The single-cell and spatial transcriptomics data of human embryonic tooth development (stages 17–24 PCW) are available in the Mendeley Data repository under https://doi.org/10.17632/v3wgx8pm5y.126 (https://data.mendeley.com/datasets/v3wgx8pm5y/1). The young dental pulp single-cell data are available in the Gene Expression Omnibus (GEO) database under accession numbers GSE202476 and GSM4365609. Source data are provided with this paper.
Code availability
The code in this study is available on GitHub at https://github.com/weiwei2012/NCOMMS-2538526, and the pipelines are detailed in the Methods.
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Acknowledgements
We thank members of Beijing Laboratory of Oral Health for inspiring discussions. We sincerely thank Dr. Junjun Jing, Dr. Zhen Huang, and Dr. Min Liu for their valuable guidance. We also thank Dr. Chenjie Zhang and Dr. Rong Kang for their valuable help with the experiments. This work was supported by the National Key Research and Development Program (2022YFA1104401 to Zhipeng Fan); Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (JYB2025XDXM610 to S.W.); Beijing Municipal Government grant (Beijing Laboratory of Oral Health, PXM2021-014226-000041 to S.W.); Beijing Municipal Government (Beijing Scholar Program, PXM2021-014226-000020 to S.W.); National Natural Science Foundation of China (82030031 to S.W., 92149301 to S.W., 81991504 to Yi Liu, L2224038 to S.W., 82270945 to R.Z.); Innovation Research Team Project of Beijing Stomatological Hospital, Capital Medical University (CXTD202201 to S.W.); Chinese Research Unit of Tooth Development and Regeneration, Academy of Medical Sciences (2019-12M-5-031 to S.W.); Beijing Natural Science Foundation General Program (7252167 to R.Z.); Young Scientist Program of Beijing Stomatological Hospital, Capital Medical University (YSP202314 to W.W.).
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Conceptualization: S.W., R.Z., W.W., C.W. Collected and analyzed scRNA-seq data: W.W., C.W., R.Z., Z.S. Collected and analyzed image and ST data: W.W., C.W., R.Z., Z.S. Methodology: W.W., C.W., J.S., M.H., X.G., H.Z., C.Z., J.W., Lei H., L.L., Y.Z., Lina H. Funding acquisition: S.W., R.Z., W.W. Writing—original draft: W.W., C.W. Writing—review & editing: S.W., X.W., Z.S., R.Z., W.W., C.W.
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Wei, W., Wu, C., Sun, J. et al. Spatiotemporal interplay between epithelial and mesenchymal cells drives human dentinogenesis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69545-3
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DOI: https://doi.org/10.1038/s41467-026-69545-3
