Spatiotemporal interplay between epithelial and mesenchymal cells drives human dentinogenesis PMID: 41690906

ADC Targets in Oncology

2026-04-10

Spatiotemporal interplay between epithelial and mesenchymal cells drives human dentinogenesis

Nat Commun. 2026 Feb 14;17(1):2791. doi: 10.1038/s41467-026-69545-3.

Wei Wei ^# ¹ , Chuan Wu ^# ¹ , Jing Sun ¹ , Mengjie Han ² , Xiuge Gu ¹ , Hanzhang Zhou ² , Xiaoshan Wu ¹ ³ , Zongshan Shen ¹ ⁴ , Chunmei Zhang ¹ , Jinsong Wang ⁵ , Lei Hu ¹ , Lanrong Luo ⁶ , Yuanyuan Zhang ⁶ , Lina Hu ⁶ , Songlin Wang ⁷ ⁸ ⁹ , Ran Zhang ¹⁰ ¹¹

Affiliations

1. Laboratory of Oral Health and Homeostatic Medicine, School of Stomatology and Beijing Stomatological Hospital and Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
2. Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China.
3. Academician Workstation for Oral-Maxillofacial Regenerative Medicine, Central South University, Changsha, China.
4. Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
6. Department of Reproductive Regulation, Beijing Obstetrics and Gynecology Hospital, Beijing Maternal and Child Health Care Hospital, Capital Medical University, Beijing, China.
7. Laboratory of Oral Health and Homeostatic Medicine, School of Stomatology and Beijing Stomatological Hospital and Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China. [email protected].
8. Academician Workstation for Oral-Maxillofacial Regenerative Medicine, Central South University, Changsha, China. [email protected].
9. Laboratory of Oral Homeostatic Medicine, School of Medicine and SUSTech Homeostatic Medicine Institute (SHMI), Southern University of Science and Technology, Shenzhen, China. [email protected].
10. Laboratory of Oral Health and Homeostatic Medicine, School of Stomatology and Beijing Stomatological Hospital and Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China. [email protected].
11. Department of Oral Pathology, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China. [email protected].
# Contributed equally.

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.