Adipose Mesenchymal Stem Cell-derived Exosomes Rescue Mitochondrial Function through SIRT1 to Improve Diabetic Wound Healing

Abstract

Background Diabetic wounds represent the most common type of chronic wounds. Persistent inflammation and elevated oxidative stress are hallmark features of chronic wounds, where macrophage phenotypic polarization playing a critical role in the healing process. Although adipose-derived mesenchymal stem cell exosomes (ADSC-exos) have shown therapeutic potential for diabetic wounds, their precise mechanisms remain elucidated. Methods A streptozotocin-induced diabetic mouse model and high glucose-stimulated RAW 264.7 macrophages were utilized to mimic diabetic microenvironments. Wound tissues were collected from patients with diabetic foot ulcer. A skin incision model was established in mice and ADSC-exos were given subcutaneously. Streptozotocin-induced diabetic myeloid-specific sirt1−/− mice SIRT1 siRNA-transfected macrophages were employed to investigate the role of SIRT1 in vivo and in vitro. Wound healing rates were quantified. Mitochondrial function, lysosomal activity, autophagy flux, and inflammation status were systematically assessed. Results In diabetic mice and high glucose-treated macrophages, lysosomal dysfunction preceded mitochondrial and autophagy flux impairments. SIRT1 expression was significantly reduced in both diabetic wound tissues and macrophages, accompanied by M1 macrophage polarization. SIRT1 interference experiments revealed that the impact of ADSC-exos on mitochondrial function, autophagy flux, and inflammatory response were partially dependent on SIRT1. Notably, the therapeutic effects of ADSC-exos on mitochondrial and autophagic pathways were markedly attenuated upon SIRT1 suppression. Conclusions These findings demonstrate that ADSC-exos promotes diabetic wound healing by restoring mitochondrial function and autophagy via SIRT1 activation. These findings highlight the therapeutic potential of ADSC-exos and provide a mechanistic foundation for future exosome engineering strategies.