Resveratrol-Pretreated Adipose-Derived Mesenchymal Stem Cell Exosomes Regulate Macrophage Polarization via PI3K/AKT Signaling Pathway

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Background Diabetic wounds exhibit persistent inflammation and impaired tissue repair. Excessive M1 macrophage polarization contributes to delayed healing. Exosomes derived from adipose-derived mesenchymal stem cells (ADSCs) are promising cell-free therapies, and resveratrol (RES) enhances stem cell functions. This study investigated whether exosomes from RES-pretreated ADSCs (RES-exo) promote diabetic wound healing by regulating macrophage polarization through the PI3K/AKT pathway. Methods Human ADSCs were pretreated with RES for exosome isolation. The effects of ADSC-derived exosomes (ADSC-exo) and RES-exo on lipopolysaccharide-induced M1 macrophage polarization were assessed by immunofluorescence staining, quantitative real-time PCR, enzyme-linked immunosorbent assay, and Western blotting. The PI3K agonist 740 Y-P was used for pathway validation. Therapeutic effects were evaluated in db/db diabetic mice. Results Both ADSC-exo and RES-exo inhibited M1 macrophage polarization and reduced pro-inflammatory mediator expression, with RES-exo showing stronger effects. RES-exo regulated PI3K/AKT phosphorylation and suppressed excessive M1 activation. In diabetic mice, RES-exo accelerated wound closure, enhanced collagen deposition and angiogenesis, and reduced inflammation compared with ADSC-exo and controls. Conclusion RES pretreatment enhances ADSC-exo therapeutic efficacy. RES-exo promotes diabetic wound healing by modulating macrophage polarization through PI3K/AKT signaling regulation, indicating its potential as a cell-free therapy. However, the responsible exosomal cargos and long-term efficacy and safety require further investigation.

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