Periodontal ligament stem cell-derived exosomal miR-378a programs osteogenic commitment via DAZAP2/SMAD signaling

Functional recovery of the periodontium remains a major clinical challenge. To harness the therapeutic potential of extracellular vesicles (EVs) derived from human periodontal ligament mesenchymal stem cells (hPDL-MSC), we identified and characterized the encapsulated miR-378a as a pivotal regulator associated with osteogenic commitment. hPDL-MSC and derivative EVs were dynamically examined throughout osteogenesis, revealing a temporal and progressive enrichment pattern. Mechanistically, integrative microarray, RNA sequencing, bioinformatic analysis, and functional assays established PIM2 and DAZAP2 as direct targets of miR-378a. Overexpression of miR-378a post-transcriptionally suppressed DAZAP2, leading to enhanced nuclear translocation of phosphorylated-SMAD1/5/9 and subsequent activation of canonical BMP signaling. Rescue experiments reinforced the essential role of the miR-378a-DAZAP2-SMAD axis in osteogenic differentiation. Collectively, our findings delineate the molecular pathway triggered by hPDL-MSC-derived exosomal miR-378a and provide new mechanistic insights into EV-mediated modulation of stem cell fate.