ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Chromosome and Chromatin Biology
This article is part of the Research TopicChromatin Modifications and Gene Expression: From Mechanisms to Therapeutic Implications in DiseaseView all 7 articles
Mandibular extracellular vesicles mediate morphogenesis and mineralization of tooth germs in miniature swine through the miR-206/HDAC4 signaling axis
Provisionally accepted
- 1First Hospital of Shanxi Medical University, Taiyuan, China
- 2Shanxi Medical University and Hospital of Stomatology, Taiyuan, China
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Reciprocal communication between odontogenic tissues underpins the complexity of tooth morphogenesis. Despite the mandible serving as the developmental niche and functional platform for tooth germs, their reciprocal signaling mechanisms remain underexplored. Histone acetylation plays a pivotal role in maintaining long-term regulatory equilibrium and physiological homeostasis by establishing stable gene expression patterns. However, whether stable histone acetylation signatures exist during tooth germ morphogenesis and how they might ensure developmental fidelity remain unreported. Here, we investigated the epigenetic role of the mandible in early tooth development. We isolated extracellular vesicles (EVs) from the mandible of E40 miniature pigs. Bioinformatic analysis revealed that these EVs carried miR-206 as a key regulatory molecule, with histone deacetylase 4 (HDAC4) predicted to be a potential downstream target. We confirmed this targeting relationship in vitro using dual-luciferase reporter assays, qRT-PCR, and Western blotting. For in vivo validation, tooth germs were transduced with lentiviral vectors to achieve overexpression or knockdown of miR-206/HDAC4, followed by subcutaneous transplantation into nude mice. The harvested tooth germs were subjected to stereomicroscopic morphological analysis, micro-CT-based 3D reconstruction with mineralization quantification, and histogenetic evaluation using H&E staining. Both in vivo and in vitro results demonstrated that miR-206 within mandibular-derived EVs acted as a critical regulator by suppressing HDAC4 expression, thereby epigenetically mediating morphogenesis and mineralization during early tooth development. These findings redefine the mandible as an active epigenetic modulator of odontogenesis via the exosomal miR-206/HDAC4 signaling axis. This vesicle-mediated mechanism enables long-range delivery of epigenetic effectors, revealing a paradigm shift in understanding tooth development and identifying a druggable target for tooth regeneration.
Keywords: tooth development, Mandible, miR-206, HDAC4, Epigenetic regulation
Received: 11 Dec 2025; Accepted: 11 Dec 2025.
Copyright: © 2025 Cao, Ma, Song, Gao, Liu, Du and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaojun Sun
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