Therapeutic angiogenesis using stem cell-derived extracellular vesicles: an emerging approach for treatment of ischemic diseases

Abstract

Ischemic diseases, which are caused by a reduction of blood supply that results in reduced oxygen transfer and nutrient uptake, are becoming the leading cause of disabilities and deaths. Therapeutic angiogenesis is key for the treatment of these diseases. Stem cells have been used in animal models and clinical trials to treat various ischemic diseases. Recently, the efficacy of stem cell therapy has increasingly been attributed to exocrine functions, particularly extracellular vesicles. Extracellular vesicles are thought to act as intercellular communication vehicles to transport informational molecules including proteins, mRNA, microRNAs, DNA fragments, and lipids. Studies have demonstrated that extracellular vesicles promote angiogenesis in cellular experiments and animal models. Herein, recent reports on the use of extracellular vesicles for therapeutic angiogenesis during ischemic diseases are presented and discussed. We believe that extracellular vesicles-based therapeutics will be an ideal treatment method for patients with ischemic diseases.

Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis

“…Lipids are also an integral part of EVs, and several studies have described EV lipid composition. EVs are rich in cholesterol, phospholipid (phosphatidylserine, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol), sphingomyelin, glycosphingolipids, diglyceride, polyglycerol, and ganglioside GM3 [88][89][90]. Specific lipids are enriched in EVs compared with their parent cells.…”

“…EV uptake can also be affected by lipid composition, with lipid rafts allowing the EVs to fuse into recipient cells [89]. As a result of EVs' high lipid content, they have an inherent capacity to pass through biological barriers and escape from phagocytosis by the reticuloendothelial system, while being biocompatible and immunologically inert [88,95].…”

Umbilical Cord Mesenchymal Stem Cell-Derived Nanovesicles Potentiate the Bone-Formation Efficacy of Bone Morphogenetic Protein 2

“…Both osteoblastic differentiation of MSCs and angiogenesis promote in vivo bone formation [ 10 , 28 ]. The stimulatory effects of exosomes secreted from MSCs on angiogenesis and osteogenesis have been demonstrated in previous studies [ 28 , 35 ]. Exosomal miRNAs such as miR-129, miR-136, and the miR-17-92 cluster promote endothelial cell proliferation and vessel formation [ 28 ].…”

“…Exosomal miRNAs such as miR-221, miR-155, miR-885-5p, miR-181a, and miR-320c are downregulated during the osteoblastic differentiation of MSCs [ 28 ]. Furthermore, UCMSCs are known to express pro-angiogenic factors, such as VEGF [ 35 ]. In this study, we used UCMSC-derived NVs, which were produced by extrusion of UCMSCs, rather than exosomes secreted from UCMSCs.…”

“…Potential limitations of NVs should be considered for the clinical application of NVs. Exosomes have in vivo limitations of their short half-life and rapid clearance by the immune system [ 35 ]. As NVs are characteristically similar to exosomes, the stability and retention ability of NVs in vivo is important for clinical applications.…”