2. Academic Validation
  3. hPDLSC-ApoEVs attenuate periodontitis and enhance bone regeneration via NF-κB/S100A9-Mediated M2 macrophage polarization

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

  • Stem Cell Res Ther. 2025 Sep 26;16(1):508. doi: 10.1186/s13287-025-04617-7.
Zeyu Zhang # 1,  Liting Zeng # 1,  Yang Yu # 2,  Zidan Xu 1,  Guanxiong Zhu 1,  Jinlong Weng 1,  Junyi Xia 1,  Weijie Peng 3,  Qin Dong 1,  Yuanyuan Li 1,  Lingmin Zhang 4 5,  Lu Liang 6 7,  Janak Lal Pathak 8,  Lina Yu 9
Affiliations

Affiliations

  • 1 Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182, Guangdong, People's Republic of China.
  • 2 Department of Sports and Health, Guangzhou Sport University, Guangzhou, 510500, Guangdong, People's Republic of China.
  • 3 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, People's Republic of China.
  • 4 Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182, Guangdong, People's Republic of China. zhanglm@gzhmu.edu.cn.
  • 5 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, People's Republic of China. zhanglm@gzhmu.edu.cn.
  • 6 Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182, Guangdong, People's Republic of China. lliangaa@gzhmu.edu.cn.
  • 7 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, People's Republic of China. lliangaa@gzhmu.edu.cn.
  • 8 Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182, Guangdong, People's Republic of China. j.pathak@gzhmu.edu.cn.
  • 9 Department of Preventive Dentistry, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182, Guangdong, People's Republic of China. yulina@gzhmu.edu.cn.
  • # Contributed equally.
PMID: 41013784 DOI: 10.1186/s13287-025-04617-7
Abstract

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-treated macrophage-conditioned medium robustly promoted osteogenic differentiation of hPDLSCs in vitro. Finally, we verified these results in the periodontitis model of male C57BL/6 mice. Local injection of hPDLSCs-ApoEVs facilitated macrophage M2 polarization, alleviated periodontitis, and restored alveolar bone.

Conclusion: In conclusion, these findings provide new evidence for the clinical application of hPDLSCs-ApoEVs in periodontitis treatment via macrophage immune modulation-mediated alveolar bone restoration.

Keywords

Apoptosis; Extracellular vesicles; Periodontal ligament stem cells; Periodontal tissue regeneration; Periodontitis.

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