Inhibition of miR-615-3p enhances dentinogenesis in scaps via PVT1-mediated mitochondrial regulation

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BACKGROUND: Mesenchymal stem cells (MSCs) are critical for dental tissue regeneration, yet their differentiation potential is tightly regulated by microRNAs (miRNAs). This study aimed to investigate the role of miR-615-3p in regulating odontogenic differentiation in stem cells from the apical papilla (SCAPs), offering insights into potential applications for enhancing dental tissue regeneration and repair. METHODS: Quantitative PCR (qPCR), Western blot analysis, alkaline phosphatase (ALP) activity assay, and Alizarin Red staining (ARS) were performed to assess odontogenic differentiation following miR-615-3p modulation in SCAPs. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels, membrane potential, and respiratory activity. In vivo, SCAPs with miR-615-3p modulation were transplanted into rabbit extraction sockets to examine dentin-like tissue formation. RESULTS: miR-615-3p was significantly downregulated in SCAPs compared to umbilical cord mesenchymal stem cells (WJCMSCs) and further decreased during mineralization induction, suggesting its negative regulatory role in odontogenic differentiation. Inhibition of miR-615-3p enhanced ALP activity, mineralization, and odontogenic marker expression both in vitro and in vivo. Proteomic analysis revealed that miR-615-3p inhibition improved mitochondrial function by reducing ROS levels and increasing mitochondrial function. Further Competing Endogenous RNA Sequencing(ceRNA-seq) analysis identified PVT1 as a downstream target of miR-615-3p. PVT1 overexpression promoted odontogenic differentiation and mitochondrial homeostasis, while its knockdown impaired these processes. Collectively, the miR-615-3p/PVT1 axis emerged as a critical regulator of dentinogenesis through mitochondrial modulation. CONCLUSIONS: Inhibiting miR-615-3p fosters dentinogenesis through PVT1-mediated mitochondrial regulation in SCAPs. These findings highlight the miR-615-3p/PVT1 axis as a promising target for enhancing dentin tissue engineering applications.

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