Stem cell-derived extracellular vesicle therapy for acute brain insults and neurodegenerative diseases

Abstract

Stem cell-based therapy is a promising approach for treating a variety of disorders, including acute brain insults and neurodegenerative diseases. Stem cells such as mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs), circular membrane fragments (30 nm-1 μm) that are shed from the cell surface, carrying several therapeutic molecules such as proteins and microRNAs. Because EV-based therapy is superior to cell therapy in terms of scalable production, biodistribution, and safety profiles, it can be used to treat brain diseases as an alternative to stem cell therapy. This review presents evidences evaluating the role of stem cell-derived EVs in stroke, traumatic brain injury, and degenerative brain diseases, such as Alzheimer's disease and Parkinson' disease. In addition, stem cell-derived EVs have better profiles in biocompatibility, immunogenicity, and safety than those of small chemical and macromolecules. The advantages and disadvantages of EVs compared with other strategies are discussed. Even though EVs obtained from native stem cells have potential in the treatment of brain diseases, the successful clinical application is limited by the short half-life, limited targeting, rapid clearance after application, and insufficient payload. We discuss the strategies to enhance the efficacy of EV therapeutics. Finally, EV therapies have yet to be approved by the regulatory authorities. Major issues are discussed together with relevant advances in the clinical application of EV therapeutics. [BMB Reports 2022; 55(1): 20-29].

Fig. 1

Association between elevated levels of circular extracellular vesicles (EVs) and stroke outcome after mesenchymal stem cell (MSC) injection. Modified from Bang et al. (10) The levels of circulating EVs increased im-mediately after intravenous injection of autologous MSCs (A and B), but not after placebo treatment (C, right lanes). Although patients of the MSC group re-ceived the same number of MSCs (1 × 10⁶ cells/kg), the levels of circulating EVs were varied among patients; (A) marked increase of EV levels in patients who showed clinically significant improvement, and (B) lesser degree of increase in those who showed no clinically significant improvement. The circulating EVs levels were correlated with improvement in MRI indices of neuroplasticity as well as in motor function.

Fig. 2

Surface molecules and cargo related to efficacy and biodistribution of stem cell-derived extracellular vesicles (EVs).