Sri Tummala

Background: Diabetic foot ulcers (DFU) are chronic, treatment-refractory wounds that develop in 15–25% of patients with diabetes during their lifetime and remain the leading cause of non-traumatic lower-extremity amputation.¹ Healing fails because chronic hyperglycemia suppresses PI3K/AKT, eNOS, and VEGF angiogenic signaling, sustains pro-inflammatory cytokines such as TNF-α and IL-6, and disrupts extracellular matrix remodeling.^2,3 Standard care, offloading, debridement, antibiotics, and revascularization, does not correct these molecular defects, leaving many ulcers refractory to treatment.¹ Mesenchymal stem cell (MSC) derived exosomes, 30–150 nm vesicles that deliver miRNA, protein, and lipid cargo to recipient cells, have emerged as a cell-free regenerative platform whose contents can be reprogrammed by preconditioning the parent MSC.^2,3 However, the exosomal miRNAs and signaling axes most effective at restoring diabetic wound angiogenesis remain incompletely defined.³

Objective: This narrative review evaluates how preconditioning MSCs with FDA-approved drugs enriches exosomal miRNA cargo, particularly miR-221-3p, to suppress PTEN and reactivate the AKT/eNOS axis in DFU, and compares this with alternative miRNA-target axes that drive angiogenesis through parallel pathways.

Search Methods: A PubMed search was conducted for articles published between 2017 and 2025 using the MeSH terms and keywords: “diabetic foot ulcer,” “mesenchymal stem cells,” “exosomes,” “microRNAs,” “miR-221-3p,” “PTEN,” “AKT,” “eNOS,” “angiogenesis,” “atorvastatin,” and “empagliflozin.” Five primary research studies and four review articles met inclusion criteria.

Results: Shen et al. demonstrated that high glucose downregulates the histone methyltransferase SET8, reducing H4K20 monomethylation at the PTEN promoter and elevating PTEN expression in HUVECs, STZ-induced diabetic rat aortic tissue, and peripheral blood mononuclear cells of diabetic patients, establishing an epigenetic basis for suppressed AKT/eNOS signaling.⁴ Yu et al. showed that exosomes from atorvastatin-pretreated bone marrow MSCs (ATV-Exos) were selectively enriched in miR-221-3p, which silenced PTEN, restored p-AKT and p-eNOS, and rescued HUVEC proliferation, migration, tube formation, and VEGF secretion under high glucose; in STZ diabetic rats, ATV-Exos accelerated wound closure and increased CD31⁺ vessel density.⁵ Yu et al. (2022) identified HIPK2 as a second direct target of miR-221-3p via dual-luciferase reporter assay, and miR-221-3p agomir injection accelerated wound closure with reduced HIPK2 and increased VEGF in STZ diabetic mice.⁶ Che et al. demonstrated that adipose-derived MSC exosomes deliver miR-146a-5p, which suppresses JAZF1 and upregulates VEGFA through a pathway distinct from PTEN/AKT; HAMA hydrogel–embedded exosomes outperformed bolus injection in db/db mice, improving CD31⁺ vessel formation and collagen deposition.⁷ Wang et al. extended the preconditioning strategy with empagliflozin, an SGLT2 inhibitor: EMPA-Exos reduced PTEN, increased p-PI3K/p-AKT/HIF-1α/VEGF, suppressed NF-κB–mediated inflammation, and accelerated wound closure with mature CD31⁺/α-SMA⁺ vessels, effects abolished by the PI3K inhibitor LY294002, confirming pathway dependence.⁸

Conclusion: Hyperglycemia-driven epigenetic upregulation of PTEN is a defect in DFU angiogenesis, and MSC-derived exosomes engineered to deliver miR-221-3p (targeting PTEN and HIPK2) or miR-146a-5p (targeting JAZF1) restore vascular regeneration in preclinical models.^5–8 Because miR-221-3p suppresses two anti-angiogenic brakes simultaneously, it is a particularly attractive cargo, and two clinically established diabetes drugs, atorvastatin and empagliflozin, can serve as MSC preconditioning agents that lower translational barriers.^5,8 Future work may standardize exosome production and dosing, evaluate multi-miRNA cargo combinations for synergistic effects, and consider advancing preconditioned MSC exosomes into clinical trials for DFU patients.^3,9

Works Cited

1. Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: a review. JAMA. 2023;330(1):62-75. doi:10.1001/jama.2023.10578
2. Wang H, Wu S, Bai X, et al. Mesenchymal stem cell-derived exosomes hold promise in the treatment of diabetic foot ulcers. Int J Nanomedicine. 2025;20:5837-5857. doi:10.2147/IJN.S516533
3. Chen WT, Luo Y, Chen XM, Xiao JH. Role of exosome-derived miRNAs in diabetic wound angiogenesis. Mol Cell Biochem. 2024;479(10):2565-2580. doi:10.1007/s11010-023-04874-1
4. Shen X, Chen X, Wang J, et al. SET8 suppression mediates high glucose-induced vascular endothelial inflammation via the upregulation of PTEN. Exp Mol Med. 2020;52(10):1715-1729. doi:10.1038/s12276-020-00509-3
5. Yu M, Liu W, Li J, et al. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res Ther. 2020;11(1):350. doi:10.1186/s13287-020-01824-2
6. Yu Q, Liu L, Zhang X, et al. MiR-221-3p targets HIPK2 to promote diabetic wound healing. Microvasc Res. 2022;140:104306. doi:10.1016/j.mvr.2021.104306
7. Che D, Xiang X, Xie J, Chen Z, Bao Q, Cao D. Exosomes derived from adipose stem cells enhance angiogenesis in diabetic wound via miR-146a-5p/JAZF1 axis. Stem Cell Rev Rep. 2024;20(4):1026-1039. doi:10.1007/s12015-024-10685-8
8. Wang H, Bai Z, Qiu Y, et al. Empagliflozin-pretreated MSC-derived exosomes enhance angiogenesis and wound healing via PTEN/AKT/VEGF pathway. Int J Nanomedicine. 2025;20:5119-5136. doi:10.2147/IJN.S512074
9. Jiao YR, Chen KX, Tang X, et al. Exosomes derived from mesenchymal stem cells in diabetes and diabetic complications. Cell Death Dis. 2024;15:271. doi:10.1038/s41419-024-06659-w