hPDLSC-ApoEVs attenuate periodontitis and enhance bone regeneration via NF-κB/S100A9-Mediated M2 macrophage polarization

作者：Zeyu Zhang, Liting Zeng, Yang Yu, Zidan Xu, Guanxiong Zhu, Jinlong Weng, Junyi Xia, Weijie Peng, Dong Qin, Yuanyuan Li, Lingmin Zhang, Lu Liang, Janak L. Pathak, Lina Yu · 发表于：Stem Cell Research & Therapy · 年份：2025 · DOI：10.1186/s13287-025-04617-7 · 被引用次数：6 · 研究领域：Oral microbiology and periodontitis research、Extracellular vesicles in disease、Bone and Dental Protein Studies

BACKGROUND: Periodontitis is the most prevalent oral disease worldwide, leading to inflammation, alveolar bone loss, and tooth loss. Mesenchymal stem cells (MSCs) transplantation has the potential to alleviate periodontitis and restore alveolar bone, but numerous studies have found that transplanted MSCs undergo apoptosis, releasing apoptotic extracellular vesicles (ApoEVs). Human periodontal ligament stem cells (hPDLSCs) ApoEVs have immunomodulatory and tissue regenerative potential. Still, their role in periodontitis treatment and alveolar bone restoration has not been investigated yet. METHODS: The study isolated hPDLSCs-ApoEVs and investigated the modulatory effect on macrophaghe. We explored the specific molecular mechanisms of hPDLSC-ApoEVs in regulating macrophage polarization in vitro through mRNA-seq and inhibitors. Co-culture experiment demonstrated that hPDLSC-ApoEVs promoted hPDLSC osteogenic differentiation by regulating macrophage polarization. Finally, we verified that hPDLSC-ApoEVs inhibited periodontitis-induced periodontal tissue defects and promoted periodontal bone tissue regeneration in vivo. RESULTS: This study found that hPDLSCs-ApoEVs regulate M0 to anti-inflammatory M2 macrophage polarization, as indicated by the upregulation of CD163, IL-10, and ARG1. hPDLSCs-ApoEVs activated NF-κB signaling that upregulated S100A9 in macrophages. hPDLSCs-ApoEVs failed M2 macrophage polarization during inhibition of NF-κB or S100A9. Furthermore, hPDLSCs-ApoEVs-treate...