Adipose-derived mesenchymal stem cell exosomes enhance diabetic wound healing via the amelioration of fibroblast senescence through the SMARCAL1-Drp1 signaling pathway

Abstract

Delayed healing of diabetic wounds (DW) represents a significant complication among diabetic patients, for which current therapeutic approaches remain suboptimal. Accumulating evidence indicates that fibroblast senescence plays a critical role in the impaired healing of diabetic wounds. Abnormal mitochondrial morphology has long been associated with cellular senescence and age-related pathologies, suggesting that mitochondrial dynamics are compromised during senescence. In this study, we explored the potential mechanisms through which adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) facilitate diabetic wound repair. We initially confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues. Subsequent investigations demonstrated that exosomes derived from adipose-derived stem cells can effectively alleviate fibroblast senescence. In-depth mechanistic analyses revealed that these exosomes suppress the expression of SMARCAL1, a chromatin remodeling protein, thereby enhancing the transcription of mitochondrial dynamin-related protein 1 (Drp1), and ultimately restoring mitochondrial dynamics and alleviating senescence in human dermal fibroblasts (HDFs). In vivo experiments further demonstrated that exosome administration significantly reduced HDFs senescence and accelerated wound healing in a diabetic mouse model. Collectively, our findings suggest that ADSC-Exos promote diabetic wound healing by mitigating HDFs senescence via the SMARCAL1-Drp1-mitochondrial dynamics pathway. This study elucidated the molecular mechanisms underlying exosome-mediated fibroblast senescence rescue and proposed a novel therapeutic strategy for diabetes-related wound management through targeted clearance of senescent cells.