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 in Gansu Province announced on July 31 that they have developed a new type of extracellular vesicle derived from three-dimensional cultured adipose stem cells. These vesicles showed promise in accelerating the healing of diabetic wounds across several preclinical models.
The study addressed challenges associated with diabetic foot ulcers, which are difficult to heal due to prolonged inflammation, poor circulation, and impaired angiogenesis. The researchers investigated whether extracellular vesicles released by self-feeder layer three-dimensional cultured adipose stem cells could reverse aging in microvascular endothelial cells and improve wound repair under diabetic conditions. Their approach combined analysis of human tissue samples, experiments on cultured endothelial cells exposed to high glucose levels, wound healing studies in diabetic mice and miniature pigs, as well as fat graft experiments.
Using single-cell RNA sequencing on tissue from diabetic foot ulcers, the team found significant senescence-related changes among microvascular endothelial populations. They then produced three-dimensional adipose stem cell-derived extracellular vesicles (tdASC-EVs) and tested their effects. In human dermal microvascular endothelial cells exposed to high glucose environments—a model for diabetes—tdASC-EVs reduced markers of cellular aging and oxidative damage while improving mitochondrial function and blood vessel formation.
Mechanistic studies indicated that tdASC-EVs reactivated the PI3K/AKT/mTOR/4EBP1 signaling pathway necessary for protein translation within these cells. Inhibiting this pathway diminished the benefits observed with tdASC-EV treatment; conversely, mimicking phosphorylation restored them. Proteomic analysis identified over 2,000 differentially expressed proteins involved in regenerative processes.
In animal models—including both mice and Bama miniature pigs—the treatment accelerated wound closure rates compared to conventional therapies using two-dimensional-cultured mesenchymal stem cell vesicles. Treated wounds displayed improved blood perfusion, increased neovascularization marked by CD31-positive vessels, and reduced scarring indicators such as p16 protein expression and collagen organization issues.
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 but highlight that future research is needed before clinical application.
