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. 2025 Aug;52(8):1196-1210.
doi: 10.1111/jcpe.14184. Epub 2025 May 19.

Exosomes Derived From Human Gingival Mesenchymal Stem Cells Induce Metabolic Reprogramming of Inflammatory Macrophages

Jialu Wang  1   2 , Yingzhe Hu  3 , Zhiguo Wang  4 , Chun Fan  1 , Ye Liu  1 , Yutong Xie  1   2 , Lubin Liu  1   2 , Jingshu Yang  1   2 , Quanchen Xu  1
Affiliations

Exosomes Derived From Human Gingival Mesenchymal Stem Cells Induce Metabolic Reprogramming of Inflammatory Macrophages

Jialu Wang et al. J Clin Periodontol. 2025 Aug.

Abstract

Aim: To investigate the influence and mechanism of exosomes derived from human gingival mesenchymal stem cells (GMSC-Exo) regulating macrophage polarisation through metabolic reprogramming.

Materials and methods: Human acute monocytic leukaemia cells (THP-1)-derived macrophages were treated with GMSC-Exo or Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) in vitro. Metabolic inhibitors were used to study the role of metabolic reprogramming in GMSC-Exo-induced polarisation, while the hypoxia-inducible factor-1 alpha (HIF-1α) modulators were employed to explore the HIF-1α signalling pathway's impact on macrophage metabolic reprogramming. The impact of GMSC-Exo on periodontitis and macrophage metabolism was assessed using a rat model in vivo.

Results: In vitro experiments confirmed that GMSC-Exo promoted the polarisation of macrophages from pro-inflammatory M1 type (classically activated) to anti-inflammatory M2 type (alternatively activated) by promoting metabolic reprogramming (glycolysis to oxidative phosphorylation). In this process, the activation of the HIF-1α signalling pathway was inhibited. In vivo experiments revealed that GMSC-Exo could regulate the inflammatory microenvironment of periodontal tissue and the metabolic pattern of macrophages.

Conclusion: By inhibiting the activation of HIF-1α signalling pathway, GMSC-Exo trigger metabolic reprogramming in macrophages, thereby regulating the macrophage transformation from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. This change enhances the local inflammatory environment, aiding tissue repair and regeneration.

Keywords: exosomes; macrophages; metabolic reprogramming; periodontitis.

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