Optimizing adipose-derived stem cell therapy for diabetic foot ulcers.

BACKGROUND: Diabetic foot ulcers (DFUs) are a severe complication of diabetes and a leading cause of lower limb amputation due to impaired wound healing. Adipose-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic option for DFUs because of their angiogenic, immunomodulatory, and regenerative properties. However, studies on the molecular mechanisms and regulatory pathways of ADSCs in DFUs are limited. AIM: To investigate the dose-response relationship, the optimal administration route, persistence, and molecular mechanisms of ADSCs in DFU healing. METHODS: In this study, human ADSCs were isolated and cultured, and their differentiation potential was characterized. A DFU mouse model was established to evaluate the dose-dependent effects and persistence of ADSCs administered subcutaneously or intramuscularly. Wound closure rate, angiogenesis, inflammation, and collagen deposition were assessed in the ADSC-treated and model groups. Additionally, in vitro experiments using human dermal fibroblasts and endothelial cells were conducted to elucidate the molecular mechanisms underlying ADSC-mediated wound healing. RESULTS: ADSC treatment significantly enhanced wound closure, promoted angiogenesis, modulated inflammatory responses, and accelerated tissue regeneration in the DFU model. Notably, the therapeutic efficacy and retention of ADSCs were influenced by both dosage and administration route, with subcutaneous injection of 5 × 105 ADSCs yielding the most favorable outcomes, particularly when injected into the feet, which resulted in prolonged retention. In vitro experiments further revealed that ADSCs exert their therapeutic effects via multiple mechanisms, including phosphatidylinositol 3-kinase signaling pathway activation to enhance vascular endothelial growth factor secretion, thereby promoting angiogenesis and modulating the Notch signaling pathway in DFUs to suppress inflammation and facilitate tissue regeneration. CONCLUSION: ADSCs effectively promote DFU healing and have clinical potential as a treatment for chronic non-healing diabetic wounds. These findings provide a foundation for optimizing ADSC-based therapies for treating DFUs.