Application of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Stroke: Biodistribution and MicroRNA Study

Overview

Journal Transl Stroke Res

Publisher Springer

Date 2018 Oct 21

PMID 30341718

Citations 84

Authors

Gyeong Joon Moon

Ji Hee Sung

Dong Hee Kim

Eun Hee Kim

Yeon Hee Cho

Jeong Pyo Son

Jae Min Cha

Oh Young Bang

Affiliations

Soon will be listed here.

Abstract

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.

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References

Ratajczak M, Kucia M, Jadczyk T, Greco N, Wojakowski W, Tendera M . Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?. Leukemia. 2011; 26(6):1166-73. DOI: 10.1038/leu.2011.389. View

Liu M, Scalia R, Mehta J, Williams K . Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. Arterioscler Thromb Vasc Biol. 2012; 32(9):2113-21. PMC: 4568119. DOI: 10.1161/ATVBAHA.112.255471. View

Li W, Choi Y, Lee P, Huh K, Kang Y, Kim H . Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant. 2009; 17(9):1045-59. DOI: 10.3727/096368908786991551. View

Ophelders D, Wolfs T, Jellema R, Zwanenburg A, Andriessen P, Delhaas T . Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med. 2016; 5(6):754-63. PMC: 4878333. DOI: 10.5966/sctm.2015-0197. View

Vahidy F, Schabitz W, Fisher M, Aronowski J . Reporting Standards for Preclinical Studies of Stroke Therapy. Stroke. 2016; 47(10):2435-8. DOI: 10.1161/STROKEAHA.116.013643. View

Qi P, Cheng S, Wang H, Li N, Chen Y, Gao C . Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One. 2011; 6(12):e28486. PMC: 3234251. DOI: 10.1371/journal.pone.0028486. View

Chen X, Li Y, Wang L, Katakowski M, Zhang L, Chen J . Ischemic rat brain extracts induce human marrow stromal cell growth factor production. Neuropathology. 2003; 22(4):275-9. DOI: 10.1046/j.1440-1789.2002.00450.x. View

Metz G, Whishaw I . Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination. J Neurosci Methods. 2002; 115(2):169-79. DOI: 10.1016/s0165-0270(02)00012-2. View

Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y . MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013; 31(12):2737-46. PMC: 3788061. DOI: 10.1002/stem.1409. View

10.

Rosenblum S, Wang N, Smith T, Pendharkar A, Chua J, Birk H . Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke. 2012; 43(6):1624-31. DOI: 10.1161/STROKEAHA.111.637884. View

11.

Kim D, Seo Y, Thambi T, Moon G, Son J, Li G . Enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor-1α using a dual ionic pH-sensitive copolymer. Biomaterials. 2015; 61:115-25. DOI: 10.1016/j.biomaterials.2015.05.025. View

12.

Moon G, Shin D, Im D, Bang O, Nam H, Lee J . Identification of oxidized serum albumin in the cerebrospinal fluid of ischaemic stroke patients. Eur J Neurol. 2011; 18(9):1151-8. DOI: 10.1111/j.1468-1331.2011.03357.x. View

13.

Gyorgy B, Szabo T, Pasztoi M, Pal Z, Misjak P, Aradi B . Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011; 68(16):2667-88. PMC: 3142546. DOI: 10.1007/s00018-011-0689-3. View

14.

Li Y, Cheng Q, Hu G, Deng T, Wang Q, Zhou J . Extracellular vesicles in mesenchymal stromal cells: A novel therapeutic strategy for stroke. Exp Ther Med. 2018; 15(5):4067-4079. PMC: 5920496. DOI: 10.3892/etm.2018.5993. View

15.

Peeters Weem S, Teraa M, de Borst G, Verhaar M, Moll F . Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials. Eur J Vasc Endovasc Surg. 2015; 50(6):775-83. DOI: 10.1016/j.ejvs.2015.08.018. View

16.

Yang B, Migliati E, Parsha K, Schaar K, Xi X, Aronowski J . Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke. 2013; 44(12):3463-72. PMC: 4209211. DOI: 10.1161/STROKEAHA.111.000821. View

17.

Bang O, Kim E, Cha J, Moon G . Adult Stem Cell Therapy for Stroke: Challenges and Progress. J Stroke. 2016; 18(3):256-266. PMC: 5066440. DOI: 10.5853/jos.2016.01263. View

18.

Gyongyosi M, Wojakowski W, Lemarchand P, Lunde K, Tendera M, Bartunek J . Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. 2015; 116(8):1346-60. PMC: 4509791. DOI: 10.1161/CIRCRESAHA.116.304346. View

19.

Schwarzenbach H, da Silva A, Calin G, Pantel K . Data Normalization Strategies for MicroRNA Quantification. Clin Chem. 2015; 61(11):1333-42. PMC: 4890630. DOI: 10.1373/clinchem.2015.239459. View

20.

Xin H, Li Y, Cui Y, Yang J, Zhang Z, Chopp M . Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013; 33(11):1711-5. PMC: 3824189. DOI: 10.1038/jcbfm.2013.152. View