Placental Mesenchymal Stem Cell-Derived Extracellular Vesicles (PMSC-EVs) as an Innovative Therapy for Diabetic Wound Healing

Individuals with diabetes mellitus (DM) experience impaired wound healing, where the healing process is often compromised by a complex, hostile microenvironment characterized by persistent inflammation, high oxidative stress, and dysfunctional angiogenesis. The hyperglycemic environment damages the blood vessels and disturbs the normal hypoxia-induced upregulation of vascular endothelial growth factors, causes poor vascularization and insufficient production of new blood vessels, and leads to impaired perfusion and thickened and dysfunctional capillary basement membranes, which reduce blood flow to the wound, leading to delayed wound healing. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are the main effectors of intercellular communication and have emerged as a potent cell-free strategy for the acceleration of tissue repair. MSC-EVs can be isolated from various adult tissues, but increasing evidence suggests that placental MSC-derived EVs (PMSC-EVs) possess distinct clinical and biological advantages for enhancing diabetic wound healing. Placentas are unique cell sources for PMSCs, which can be easily acquired non-invasively from a discarded placenta and is ethically acceptable, and have superior proliferative capacity. The cargo of PMSC-derived EVs contains macromolecules such as proteins, mRNA, miRNA, and lipids, which may be tailored for fetomaternal tolerance and translates to unmatched immunomodulatory potential for resolving chronic diabetic inflammation. The PMSC-derived EVs also aid in enhancing multiple pathways, including modulation of inflammation, angiogenesis, and epithelial proliferation, that lead to increased wound healing. This article will highlight the unique advantages, specific mechanisms, and limitations of PMSC-derived EVs as an innovative non-cellular therapeutic modality in restoring vital repair processes and enhancing diabetic wound healing.