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

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.