Diabetic foot ulcers are among the most serious complications of diabetes because prolonged inflammation, poor circulation, and defective angiogenesis can leave wounds open for months and increase the risk of infection and amputation. Although extracellular vesicles from adipose-derived mesenchymal stem cells have shown regenerative potential, conventional two-dimensional culture gradually weakens stem-cell activity and secretory function. Many laboratory studies also rely on generic endothelial cells, which do not fully reproduce the behavior of the skin’s microvasculature under diabetic stress. Based on these challenges, in-depth research is needed to develop more potent extracellular vesicles and clarify how they rescue senescent human dermal microvascular endothelial cells in diabetic wounds.
Researchers from Lanzhou University Second Hospital, Xijing Hospital, Fourth Military Medical University, the Affiliated Hospital of Jiangnan University, and the Key Laboratory of Stem Cells and Gene Drugs, Gansu Province, reported (DOI: 10.1093/burnst/tkag042) the study in Burns & Trauma on June 22, 2026. They investigated whether extracellular vesicles released by self-feeder layer three-dimensional cultured adipose stem cells could reverse microvascular endothelial aging and improve diabetic wound repair. The research combined human tissue analysis, cultured endothelial cells, diabetic mouse wounds, fat graft experiments, and a diabetic Bama miniature pig wound model.
The team first used single-cell ribonucleic acid (RNA) sequencing to map endothelial populations in diabetic foot ulcer tissue and found strong senescence-related changes in the microvascular compartment. They then produced three-dimensional adipose stem cells and isolated three-dimensional adipose stem cell-derived extracellular vesicles (tdASC-EVs). In human dermal microvascular endothelial cells exposed to high glucose, tdASC-EVs reduced senescence-associated beta-galactosidase activity, lowered oxidative damage, restored mitochondrial membrane potential, and improved tube formation. Mechanistic experiments showed that the vesicles reactivated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR)/4E-binding protein 1 (4EBP1) pathway. Increased 4EBP1 phosphorylation released eukaryotic translation initiation factor 4E (eIF4E), allowing it to bind eukaryotic translation initiation factor 4G (eIF4G) and restart cap-dependent protein translation. Pathway inhibitors weakened these benefits, while a phosphorylation-mimicking 4EBP1 construct restored them. Proteomic profiling also identified 2,097 differentially expressed proteins, including cargo linked to regenerative signaling and translation. In diabetic mice, treatment accelerated wound closure, improved blood perfusion, increased cluster of differentiation 31 (CD31)-positive microvessels, reduced p16 protein expression, narrowed scars, and organized collagen. In diabetic miniature pigs, tdASC-EVs outperformed conventional adipose-derived mesenchymal stem cell extracellular vesicles, producing faster closure, denser neovascularization, less scarring, and more complete tissue regeneration.
In a summary prepared for this release, the authors said, "Diabetic wounds are not only short of new blood vessels; the endothelial cells that should build those vessels become prematurely aged and lose the ability to translate proteins needed for repair. By improving the way adipose stem cells are cultured, we generated extracellular vesicles with stronger regenerative activity. These vesicles reopened a key translation pathway, restored endothelial function, and improved both the speed and quality of healing across several preclinical models. The large-animal results are especially encouraging, although clinical safety and manufacturing consistency must still be established."
The findings support further development of tdASC-EVs as an acellular treatment for diabetic foot ulcers and possibly other diabetes-related tissue injuries marked by microvascular aging. Because extracellular vesicles can deliver regenerative signals without transplanting living cells, they may offer practical advantages for storage, dosing, and standardized production. However, the therapy remains preclinical. Future studies must identify which vesicle proteins are essential, confirm the pathway in genetically controlled models, and test long-term biodistribution, clearance, immune responses, and potential tumor-promoting effects. Larger human tissue datasets and well-designed clinical trials will also be needed to determine effective doses, treatment schedules, manufacturing standards, and whether the approach can reduce recurrence, amputation, and reconstructive surgery in patients.
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References
DOI
10.1093/burnst/tkag042
Original Source URL
https://doi.org/10.1093/burnst/tkag042
Funding information
This work was supported by grants from the National Natural Science Foundation of China (No. 82560445, 82360444), and the Key Research and Development Program of Shaanxi Province (2024SF-ZDCYL-04-10).
About Burns & Trauma
Burns & Trauma is an open access, peer-reviewed journal publishing the latest developments in basic, clinical, and translational research related to burns and traumatic injuries, with a special focus on various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, prevention, and regeneration of burns and trauma injury.