Metformin Enhances the Pro-Regenerative Function of Human Adipose-Derived Stromal Cells for Diabetic Wound Healing

Chronic wounds associated with diabetes remain a major challenge due to impaired angiogenesis, reduced fibroblast activity and dysfunction of regenerative cells. Adipose-derived mesenchymal stromal cells (ASCs) represent a promising therapeutic option; however, their regenerative potential is limited under hyperglycaemic conditions. This study investigated whether metformin could enhance ASC function and improve their therapeutic potential for tissue regeneration. Transcriptomic analysis of wound tissue identified pathways associated with angiogenesis, inflammation, extracellular matrix remodelling and cell survival, including PI3K-AKT, JAK-STAT and AGE-RAGE signalling. Functionally, metformin increased ASC proliferation in a concentration-dependent manner and promoted sustained cell expansion over time. Metformin-treated ASCs also enhanced fibroblast migration in a co-culture system, indicating improved paracrine pro-reparative signalling. Metformin further increased the secretion of angiogenic factors, including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), supporting a pro-angiogenic secretory profile. Metformin enhanced CD31 expression and tube formation capacity of ASCs under normoglycemic conditions, particularly in combination with VEGF; however, these effects were attenuated under high-glucose conditions. Additionally, metformin improved ASC adhesion to small intestinal submucosa (SIS) scaffolds and supported endothelial marker expression in a three-dimensional biomaterial environment. Collectively, these findings demonstrate that metformin promotes a pro-regenerative ASC phenotype characterized by enhanced proliferation, paracrine signalling, endothelial-associated responses and scaffold integration. However, hyperglycaemic conditions partially impair these effects, highlighting the influence of metabolic stress on regenerative responses. Overall, metformin preconditioning represents a promising strategy to enhance ASC-based therapies for chronic and diabetic wound healing.