Application of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Stroke: Biodistribution and MicroRNA Study
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Mesenchymal stem cells (MSCs) exert their therapeutic capability through a variety of bioactive substances, including trophic factors, microRNAs, and extracellular vesicles (EVs) in infarcted tissues. We therefore hypothesized that MSC-derived EVs (MSC-EVs) possess therapeutic molecules similar to MSCs. Moreover, given their nature as nanosized and lipid-shielded particles, the intravenous infusion of MSC-EVs would be advantageous over MSCs as a safer therapeutic approach. In this study, we investigated the biodistribution, therapeutic efficacy, and mode of action of MSC-EVs in a rat stroke model. MSC-EVs successfully stimulated neurogenesis and angiogenesis in vivo. When compared to the MSC-treated group, rats treated with MSC-EVs exhibited greater behavioral improvements than the control group (p < 0.05). Our biodistribution study using fluorescence-labeled MSC-EVs and MSCs demonstrated that the amounts of MSC-EVs in the infarcted hemisphere increased in a dose-dependent manner, and were rarely found in the lung and liver. In addition, MSC-EVs were highly inclusive of various proteins and microRNAs (miRNAs) associated with neurogenesis and/or angiogenesis compared to fibro-EVs. We further analyzed those miRNAs and found that miRNA-184 and miRNA-210 were essential for promoting neurogenesis and angiogenesis of MSC-EVs, respectively. MSC-EVs represent an ideal alternative to MSCs for stroke treatment, with similar medicinal capacity but an improved safety profile that overcomes cell-associated limitations in stem cell therapy.
KeywordsStroke Mesenchymal stem cells Extracellular vesicles Neurogenesis Angiogenesis MicroRNAs
G.J.M.: conception and design, manuscript writing, financial support, collection and/or assembly of data, data analysis and interpretation, administrative support, final approval of manuscript; J.H.S.: provision of study material, collection and/or assembly of data, data analysis and interpretation; D.H.K.: collection and/or assembly of data, data analysis and interpretation, provision of study material; E.H.K.: collection and/or assembly of data, data analysis and interpretation, provision of study material; Y.H.C.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.P.S.: collection and/or assembly of data, data analysis and interpretation, provision of study material; J.M.C.: collection and/or assembly of data, provision of study material; O.Y.B.: conception and design, financial support, final approval of manuscript.
This study was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry of Health & Welfare (HI14C1439, HI14C3484, HI17C1256) and Basic Science Research Program, the Ministry of Science, ICT and Future Planning (NRF-2013R1A1A2058139 and NRF-2014R1A1A1004645).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Samsung Biomedical Research Institute (SBRI, Approval No. 20140203001) and performed in accordance with the Institute of Laboratory Animal Resources (ILAR) guide. All animals were maintained in compliance with the relevant laws and institutional guidelines of the Laboratory Animal Research Center (LARC; AAALAC International approved facility, No. 001003) at the Samsung Medical Center.
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