Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

Abstract

Extracellular vesicles (EVs), which are the main paracrine components of stem cells, mimic the regenerative capacity of these cells. Stem cell-derived EVs (SC-EVs) have been used for the treatment of various forms of tissue injury in preclinical trials through maintenance of their stemness, induction of regenerative phenotypes, apoptosis inhibition, and immune regulation. The efficiency of SC-EVs may be enhanced by selecting the appropriate EV-producing cells and cell phenotypes, optimizing cell culture conditions for the production of optimal EVs, and further engineering the EVs produced to transport therapeutic and targeting molecules. Cells 2020, 9, 707 2 of 28 storage, immune rejection, gene mutation, and tumorigenesis or tumor promotion in vivo limit its application. Stem cell derived-EVs (SC-EVs), as the main paracrine executor, overcome most limitations of stem cell applications. SC-EVs have allowed major advances in preclinical or clinical studies.In this review, the potential therapeutic applications of SC-EVs in regenerative medicine are discussed and the underlying molecular mechanisms are explored. Some of the possibilities for improving their secretion and altering their components to improve their efficacy toward diverse indications and diseases are summarized. Stem Cell-Derived EVs in the Treatment of Damaged TissueNumerous preclinical trials have reported that SC-EVs can carry active molecules, such as proteins, lipids, and nucleic acids, and good therapeutic effects against various diseases regarding different systems, including the nervous system, respiratory system, circulatory system, digestive system, urinary system, and others, have been observed. Neurological SystemBrain trauma is a common event that can cause nerve damage and disability. EXs derived from human adipose mesenchymal stem cells (AdMSC-EXs) can significantly increase the number of neurons, reduce inflammation, improve sensory and cognitive function, and produce better effects than AdMSCs alone in rats that have incurred traumatic brain injury (TBI) [6]. Kim et al. indicated that systemic administration of CD63+CD81+ EVs produced by human bone marrow-derived stem cells (BMSC-EVs) decreased neuroinflammation 12 h after a TBI in a mouse model of TBI induced by a controlled cortical impact device [7]. They also found that BMSC-EV infusion preserved the pattern separation and spatial learning abilities of mice, which were demonstrated respectively by an object-based behavioral test and a water maze test [7].Stroke is the sudden rupture or occlusion of cerebral blood vessels that interrupts the blood supply. It is the main cause of death and disability in Chinese adults. Preclinical studies have shown that SC-EVs seem to be a promising candidate for stroke treatment. Xin et al. showed that infusion of BMSC-EXs enhanced oligodendrogenesis and neurogenesis, remodeled synapses, reduced the incidence of stroke, and accelerated the recovery of neurological functions in a rat model of stroke induced by transient middle cerebral artery occl...

Antiviral effects of miRNAs in extracellular vesicles against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mutations in SARS-CoV-2 RNA virus

“…Currently efforts are underway to develop lipid nanoparticles that can be delivered to target cells following intravenous (IV) injection (hepatocytes) allowing the efficient transfer of miRNA [32]. As research on extracellular vesicles advances, the paracrine and regenerative effects of stem cells mediated via EVs have been demonstrated [33]. Because EVs are natural vesicles they are considered to be safer and more effective than artificial alternatives.…”

Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier for Regenerative Medicine?

“…Generally, EVs can promote myocardial regeneration and restore cardiac Most of the literature concerning EVs released by MSCs is isolated from different tissues. That is why we barely mention the topic and for more in depth information we refer to some recent reviews [159,160].…”

“…As described above, more and more in vitro and preclinical studies have demonstrated that stem cells exert their regenerative potential via paracrine mechanisms, which include EV release. Due to their lower immunogenicity, easier handling, and having no risk of tumor formation, researchers recently focused on their potential as possible alternatives to stem cells [159,[204][205][206], studying experimental model diseases treated with MSC-EVs. To date, a total of eight clinical trials on the application of EVs for disease treatment were identified [160].…”

Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa

“…Proteins present in the extracellular BM-MSC vesicles also include signaling molecules such as mitogen-activated protein kinase (MAPK1), an enzyme expressed by the MAPK1 gene, cell adhesion mediators such as fibronectin, and surface receptors such as the PDGF receptor. MSC-derived extracellular vesicles also express regulatory molecules such as transforming GF beta (TGF-β), galectin-1, and programmed death-ligand1 (PD-L1), mediators involved in the processes of differentiation, proliferation, and cell apoptosis [ 213 , 214 ].…”