The evaluation of the use of extracellular vesicles (derived from different cellular sources and mammalian fluids) in regenerative medicine has produced interesting results. This includes their great potential for the treatment of chronic skin ulcers, which is related to their effects on migration, proliferation, inflammation and angiogenesis, among other processes. However, large-scale production of mammalian extracellular vesicles may be limited by the need to maintain cell cultures continuously, without losing their ability to secrete extracellular vesicles with regenerative capacity. This may require complex and expensive infrastructures. It is therefore necessary to identify other possible, more efficient alternatives that can be easily transferred to clinical practice. Among these substitutes are plant-derived extracellular vesicles (PDEVs). Fortunately, they resemble those of mammals, playing a role in cell communications. As expected, their compositions depend on source tissues and the physiological conditions of the plants. They may carry numerous molecules with high biological activity. Interestingly, PDEVs are easy to obtain on a large scale, have good stability and are less immunogenic than mammalian-derived EVs. Numerous preclinical studies indicate that they can enhance chronic-wound healing through their immunomodulatory and angiogenic effects, among others. Thus, this review aims to describe the current state of knowledge on the potential therapeutic use of PDEVs in wound healing. It also describes the methods of obtaining and applying them, as well as regenerative processes in which they may intervene. The information provided shows the need to continue advancing knowledge about the production, isolation and mechanisms of action of PDEVs. This will allow new effective therapeutic strategies for the treatment of chronic cutaneous ulcers to be developed.

Endothelial aging may be induced early in pathological situations. The uremic toxins indoxyl sulfate (IS) and p-cresol (PC) accumulate in the plasma of chronic kidney disease (CKD) patients, causing accelerated endothelial aging, increased cardiovascular events and mortality. However, the mechanisms by which uremic toxins exert their deleterious effects on endothelial aging are not yet fully known. Thus, the aim of the present study is to determine the effects of IS and PC on endothelial damage and early senescence in cultured human umbilical vein endothelial cells (HUVECs). Hence, we establish an in vitro model of endothelial damage mediated by different passages of HUVECs and stimulated with different concentrations of IS and PC to evaluate functional effects on the vascular endothelium. We observe that cell passage-induced senescence is associated with apoptosis, ROS production and decreased endothelial proliferative capacity. Similarly, we observe that IS and PC cause premature aging in a dose-dependent manner, altering HUVECs’ regenerative capacity, and decreasing their cell migration and potential to form vascular structures in vitro. In conclusion, IS and PC cause accelerated aging in HUVECs, thus contributing to endothelial dysfunction associated with CKD progression.

Background/Objectives: Obesity is a major public health problem and a risk factor for numerous diseases. Furthermore, the high prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency in obese individuals promotes a state of persistent inflammation and contributes to the development of hard-to-heal skin wounds. Although calcifediol is effective in correcting this deficiency, its effect on cutaneous wound healing in obesity has not been fully established. Thus, the objective of this work has been to evaluate the impact of calcifediol treatment on wound healing in an animal model of obesity with vitamin D deficiency. Methods: Wistar rats fed a high-fat, vitamin D-deficient diet were subjected to dorsal skin wounds. One group received calcifediol treatment for 14 days. Serum 25(OH)D levels, wound closure rate, histological parameters, and molecular markers related to inflammation were analyzed. Results: Calcifediol significantly increased serum 25(OH)D levels and accelerated wound closure compared to untreated animals. It also improved re-epithelialization, reduced the depth and extent of the lesions, and promoted collagen deposition. Furthermore, it increased the expression of anti-inflammatory markers (IL-10 and CD163) and decreased the infiltration of CD68+ macrophages, indicating a more efficient resolution of the inflammatory response. Conclusions: Calcifediol supplementation improves cutaneous wound healing in obesity with 25(OH)D deficiency by accelerating wound closure, promoting extracellular matrix remodeling, and modulating the inflammatory response, supporting its use as a complementary strategy to enhance tissue repair in conditions of obesity and vitamin D deficiency.