Exosomes derived from HISLA overexpressed-adipose stem cells accelerate wound healing in diabetic foot ulcers by regulating HIF-1α signal transduction

Diabetic foot ulcers (DFUs), characterized by impaired angiogenesis and a chronic inflammatory milieu, represent a severe complication of diabetes. This study investigates the therapeutic potential of exosomes derived from HISLA-overexpressing adipose-derived stem cells (HISLA-ex) in enhancing DFU healing. In vitro, under high glucose conditions, HISLA-ex significantly elevated HISLA expression by approximately 3-fold in endothelial cells, markedly improving cell viability at 24-72 h in HMEC-1 cells, reducing pro-inflammatory cytokines IL-1 and IL-6, and enhancing tube formation capacity as evidenced by increased branching points and total tube length. Subsequently, a DFU rat model was established by inducing diabetes with streptozotocin followed by creation of a full-thickness cutaneous wound on the foot dorsum. HISLA-ex application substantially accelerated wound closure and modulated key angiogenic factors: upregulating VEGFA and ANG-1 while suppressing TSP-1. Furthermore, HISLA-ex shifted the helper T (Th)1/Th2 balance by inhibiting T-bet and pro-inflammatory cytokines (IFN-γ and TNF-α) and promoting GATA3 and anti-inflammatory cytokines (IL-4 and IL-13) in vivo and in vitro. Mechanistically, these effects were mediated through activation of the HIF-1α pathway, confirmed by both gain- and loss-of-function experiments, and abolished upon HIF-1α inhibition. Collectively, our results demonstrate that HISLA-ex synchronously promotes angiogenesis and corrects Th immune dysfunction, offering a novel RNA-based exosomal therapeutic strategy for the treatment of DFUs.