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

Senescent fibroblasts are present in substantial numbers in diabetic wound tissues.

• The study confirmed the presence of a substantial number of senescent fibroblasts in diabetic wound tissues.
• Fibroblast senescence was identified as playing a critical role in impaired healing of diabetic wounds.
• This finding established the pathological basis for investigating senescence-targeting therapies.

Adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exos) effectively alleviate fibroblast senescence in human dermal fibroblasts (HDFs).

• ADSC-Exos were shown to reduce markers of cellular senescence in HDFs.
• The anti-senescence effect was demonstrated through in vitro mechanistic analyses.
• Current therapeutic approaches for diabetic wounds were noted to remain suboptimal, motivating this investigation.

ADSC-Exos suppress SMARCAL1 expression, a chromatin remodeling protein, in human dermal fibroblasts.

• SMARCAL1 was identified as a chromatin remodeling protein whose expression is modulated by ADSC-Exos.
• Suppression of SMARCAL1 was mechanistically linked downstream to changes in mitochondrial dynamics.
• SMARCAL1 suppression was identified as a key upstream event in the exosome-mediated senescence rescue pathway.

Suppression of SMARCAL1 by ADSC-Exos enhances the transcription of mitochondrial dynamin-related protein 1 (Drp1).

• Drp1 transcription was found to be regulated by SMARCAL1 in a suppressive manner.
• ADSC-Exos-mediated reduction of SMARCAL1 led to increased Drp1 expression.
• This relationship defined a SMARCAL1-Drp1 signaling axis as central to the mechanism of action.

Enhanced Drp1 expression following ADSC-Exos treatment restores mitochondrial dynamics and alleviates senescence in HDFs.

• Abnormal mitochondrial morphology was associated with cellular senescence and age-related pathologies.
• Mitochondrial dynamics were identified as compromised during fibroblast senescence in diabetic wounds.
• Restoration of mitochondrial dynamics via Drp1 upregulation was linked to alleviation of cellular senescence in HDFs.

In vivo exosome administration significantly reduced HDF senescence and accelerated wound healing in a diabetic mouse model.

• In vivo experiments were conducted using a diabetic mouse model.
• Exosome administration significantly reduced HDFs senescence in vivo.
• Wound healing was accelerated following exosome treatment in the diabetic mouse model.
• In vivo findings corroborated the in vitro mechanistic data.

The SMARCAL1-Drp1-mitochondrial dynamics pathway represents the mechanistic basis by which ADSC-Exos promote diabetic wound healing.

• The pathway was described as: ADSC-Exos → suppression of SMARCAL1 → enhanced Drp1 transcription → restored mitochondrial dynamics → alleviated fibroblast senescence → improved wound healing.
• The study elucidated molecular mechanisms underlying exosome-mediated fibroblast senescence rescue.
• The authors proposed targeted clearance of senescent cells as a novel therapeutic strategy for diabetes-related wound management.