International Dental Journal · Published 2026-08-01 · Available online 14 Jun 2026 · Journal article · DOI 10.1016/j.identj.2026.109680 · PMID: 42288015 · PMC
Wanhao Yan, Xiaoli Guo, Bingqi Zhao, Yongkang Li, Zhe Shen, Ruitang Shi, Chen Zhang
Objectives: Odontogenic differentiation of stem cells from apical papilla (SCAPs) is critical for pulp regeneration therapy. Protein arginine methyltransferase 6 (PRMT6) plays an important role in stem cell differentiation, but the specific functions and mechanisms remain unclear. This study aimed to explore the role of PRMT6 nuclear localization sequence (NLS) in regulating SCAPs osteogenic and odontogenic differentiation and its underlying mechanism. Materials and methods: SCAPs were isolated and identified by flow cytometry. Wild-type PRMT6 and NLS-deleted PRMT6 (PRMT6ΔNLS) overexpression models were constructed via lentiviral infection. Osteogenic and odontogenic differentiation was evaluated via alkaline phosphatase staining, Alizarin Red staining, western blot, and in vivo nude mouse transplantation. Mitochondrial function was analysed by transmission electron microscopy, mitochondrial stress testing, and JC-10 membrane potential assays. Downstream gene expression and β-catenin pathway activity were examined via real-time RT-PCR, western blot, and rescue experiments were performed by exogenous Dickkopf‑1 (DKK1) supplementation. Results: PRMT6 exhibited nucleocytoplasmic redistribution during early odontogenic differentiation of SCAPs, with increased nuclear export. NLS mutation reduced PRMT6 nuclear accumulation, reversed PRMT6-mediated inhibition of in vitro mineralization and osteogenic and odontogenic marker expression, and promoted in vivo bone-/dentin-like tissue formation. Additionally, PRMT6ΔNLS rescued mitochondrial ultrastructural damage, increased OCR and mitochondrial membrane potential, and improved mitochondrial function. Mechanistically, PRMT6ΔNLS downregulated Wnt antagonist DKK1, activated the β-catenin pathway, and exogenous DKK1 abolished this pro-differentiation effect. Conclusions: PRMT6 nuclear localization is essential for its inhibitory effect on SCAPs osteogenic and odontogenic differentiation. NLS-deleted PRMT6 promotes SCAPs differentiation by rescuing mitochondrial function and activating the β-catenin pathway via downregulating DKK1. Clinical significance: This study provides a theoretical basis and potential targets for promoting dentin–pulp regeneration by modulating PRMT6 nuclear transport.
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Yan, W., Guo, X., Zhao, B., et al. (2026). Protein Arginine Methyltransferase 6 Regulated Odontogenic Differentiation and Mitochondrial Function of Stem Cells from Apical Papilla Through its Nuclear Localization Sequence via β-catenin Pathway. International Dental Journal. https://doi.org/10.1016/j.identj.2026.109680