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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320570 | GEO | 2026/02/26

REPOSITORIES: GEO

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Project description:Abstract Objectives: Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with no effective drug treatment currently available. The aberrant expressions of microRNAs (miRNAs) contribute to AAA pathogenesis. In this study, we aimed to perform miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice compared to those in control mice, and to clarify the role and mechanism of miRNA-378a-5p (miR-378a-5p) in the AAA development. Methods: We performed a comprehensive miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice and control mice. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of miR-378a-5p in the serum and aortas of AAA patients and mice. To clarify the role of miR-378a-5p in the AAA development in vivo, miR-378a-5p antagomir and angomir were administered to ApoE-/- mice using tail venous injection, followed by Angiotensin II (Ang II) infusion. Next, the role of miR-378a-5p in the phenotypic switching and migration of vascular smooth muscle cells (VSMCs) was examined in vivo and in vitro. Mechanistically, the targets of miR-378a-5p were identified by bioinformatics analysis, luciferase assay, qRT-PCR and western blot. Co-immunoprecipitation (Co-IP) assay combined with mass spectrometry were carried out for excavating potential downstream effectors. Results: The expression of miR-378a-5p was decreased in the serum and aortas of AAA patients and mice, and tumor necrosis factor-α (TNFα)-treated VSMCs. In vivo, the antagomir-378a-5p aggravated AAA formation, as evidenced by a larger maximal aortic diameter and greater medial elastin degradation than in control mice. MiR-378a-5p angomir had the opposite effect. In vitro, miR-378a-5p overexpression significantly promoted the contraction ability and suppressed the migration of VSMCs, whereas miR-378a-5p knockdown inhibited the contraction ability and increased the migration of VSMCs. Mechanistically, we discovered that miR-378a-5p played a protective role in AAA development by regulating actin-binding LIM protein 1 (ABLIM1)-megakaryoblastic leukemia 1 (MKL1) pathway. Conclusion: MiR-378a-5p exerts protective effects against AAA by maintaining VSMCs homeostasis via the ABLIM1-MKL1 pathway. Therefore, targeting miR-378a-5p may be an attractive therapeutic strategy for AAA treatment.

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

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