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Open Access 01-10-2018 | Original Article

Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model

Authors: Robin L. Webb, Erin E. Kaiser, Shelley L. Scoville, Tyler A. Thompson, Sumbul Fatima, Chirayukumar Pandya, Karishma Sriram, Raymond L. Swetenburg, Kumar Vaibhav, Ali S. Arbab, Babak Baban, Krishnan M. Dhandapani, David C. Hess, M. N. Hoda, Steven L. Stice

Published in: Translational Stroke Research | Issue 5/2018

Abstract

Over 700 drugs have failed in stroke clinical trials, an unprecedented rate thought to be attributed in part to limited and isolated testing often solely in “young” rodent models and focusing on a single secondary injury mechanism. Here, extracellular vesicles (EVs), nanometer-sized cell signaling particles, were tested in a mouse thromboembolic (TE) stroke model. Neural stem cell (NSC) and mesenchymal stem cell (MSC) EVs derived from the same pluripotent stem cell (PSC) line were evaluated for changes in infarct volume as well as sensorimotor function. NSC EVs improved cellular, tissue, and functional outcomes in middle-aged rodents, whereas MSC EVs were less effective. Acute differences in lesion volume following NSC EV treatment were corroborated by MRI in 18-month-old aged rodents. NSC EV treatment has a positive effect on motor function in the aged rodent as indicated by beam walk, instances of foot faults, and strength evaluated by hanging wire test. Increased time with a novel object also indicated that NSC EVs improved episodic memory formation in the rodent. The therapeutic effect of NSC EVs appears to be mediated by altering the systemic immune response. These data strongly support further preclinical development of a NSC EV-based stroke therapy and warrant their testing in combination with FDA-approved stroke therapies.

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Cheng NT, Kim AS. Intravenous thrombolysis for acute ischemic stroke within 3 hours versus between 3 and 4.5 hours of symptom onset. Neurohospitalist. 2015;5(3):101–9. https://doi.org/10.1177/1941874415583116.CrossRefPubMedPubMedCentral

Boyle K, Joundi RA, Aviv RI. An historical and contemporary review of endovascular therapy for acute ischemic stroke. Neurovasc Imaging. 2017;3(1):1. https://doi.org/10.1186/s40809-016-0025-2.CrossRef

Adams HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke. A guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. 2007;115(20):e478–534. https://doi.org/10.1161/circulationaha.107.181486.

Duncan PW, Zorowitz R, Bates B, Choi JY, Glasberg JJ, Graham GD, et al. Management of adult stroke rehabilitation care. A Clinical Practice Guideline. Stroke. 2005;36(9):e100–e43. https://doi.org/10.1161/01.str.0000180861.54180.ff.CrossRefPubMed

Kapral MK, Wang H, Mamdani M, Tu JV. Effect of socioeconomic status on treatment and mortality after stroke. Stroke. 2002;33(1):268–75. https://doi.org/10.1161/hs0102.101169. CrossRefPubMed

Mendis S. Stroke disability and rehabilitation of stroke: World Health Organization perspective. Int J Stroke. 2013;8(1):3–4. https://doi.org/10.1111/j.1747-4949.2012.00969.x.CrossRefPubMed

Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40(2):510–5. https://doi.org/10.1161/STROKEAHA.108.526863.

Savitz SI, Chopp M, Deans R, Carmichael ST, Phinney D, Wechsler L. Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II. Stroke. 2011;42(3):825–9. https://doi.org/10.1161/STROKEAHA.110.601914.CrossRefPubMed

Chopp M, Zhang ZG. Emerging potential of exosomes and noncoding microRNAs for the treatment of neurological injury/diseases. Expert Opin Emerg Drugs. 2015;20(4):523–6. https://doi.org/10.1517/14728214.2015.1061993.CrossRefPubMedPubMedCentral

10.

Basso M, Bonetto V. Extracellular vesicles and a novel form of communication in the brain. Front Neurosci. 2016;10:127. https://doi.org/10.3389/fnins.2016.00127.CrossRefPubMedPubMedCentral

11.

Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83. https://doi.org/10.1083/jcb.201211138.CrossRefPubMedPubMedCentral

12.

Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E. Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci. 2017;18(6) https://doi.org/10.3390/ijms18061190.

13.

Doeppner TR, Herz J, Görgens A, Schlechter J, Ludwig A-K, Radtke S, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med. 2015;4(10):1131–43. https://doi.org/10.5966/sctm.2015-0078.CrossRefPubMedPubMedCentral

14.

Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, 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. https://doi.org/10.1038/jcbfm.2013.152.CrossRefPubMedPubMedCentral

15.

Zhang Y, Chopp M, Zhang ZG, Katakowski M, Xin H, Qu C, et al. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int. 2016; https://doi.org/10.1016/j.neuint.2016.08.003.

16.

Wiklander OPB, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4. https://doi.org/10.3402/jev.v4.26316

17.

Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105–16. https://doi.org/10.1074/jbc.M112.410944.CrossRefPubMedPubMedCentral

18.

Couch Y, Akbar N, Davis S, Fischer R, Dickens AM, Neuhaus AA, et al. Inflammatory stroke extracellular vesicles induce macrophage activation. Stroke. 2017;48(8):2292–6. https://doi.org/10.1161/strokeaha.117.017236.CrossRefPubMedPubMedCentral

19.

Zhang ZG, Chopp M. Exosomes in stroke pathogenesis and therapy. J Clin Invest. 2016;126(4):1190–7. https://doi.org/10.1172/JCI81133.CrossRefPubMedPubMedCentral

20.

Lener T, Gimona M, Aigner L, Börger V, Buzas E, Camussi G, et al. Applying extracellular vesicles based therapeutics in clinical trials—an ISEV position paper. J Extracell Vesicles. 2015;4(1):30087. https://doi.org/10.3402/jev.v4.30087.CrossRefPubMed

21.

Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28(4):970–3. https://doi.org/10.1038/leu.2014.41. CrossRefPubMed

22.

Hoda MN, Fagan SC, Khan MB, Vaibhav K, Chaudhary A, Wang P, et al. A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model. Exp Transl Stroke Med. 2014;6(1):10. https://doi.org/10.1186/2040-7378-6-10.CrossRefPubMedPubMedCentral

23.

Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH, et al. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011;3(1):16. https://doi.org/10.1186/2040-7378-3-16.CrossRefPubMedPubMedCentral

24.

Shin S, Mitalipova M, Noggle S, Tibbitts D, Venable A, Rao R, et al. Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions. Stem Cells. 2006;24(1):125–38. https://doi.org/10.1634/stemcells.2004-0150.CrossRefPubMed

25.

Dhara SK, Hasneen K, Machacek DW, Boyd NL, Rao RR, Stice SL. Human neural progenitor cells derived from embryonic stem cells in feeder-free cultures. Differentiation. 2008;76(5):454–64. https://doi.org/10.1111/j.1432-0436.2007.00256.x.CrossRefPubMed

26.

Boyd NL, Robbins KR, Dhara SK, West FD, Stice SL. Human embryonic stem cell-derived mesoderm-like epithelium transitions to mesenchymal progenitor cells. Tissue Eng A. 2009;15(8):1897–907. https://doi.org/10.1089/ten.tea.2008.0351.CrossRef

27.

Hwang DW, Choi H, Jang SC, Yoo MY, Park JY, Choi NE, et al. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using (99m)Tc-HMPAO. Sci Rep. 2015;5(1):15636. https://doi.org/10.1038/srep15636.CrossRefPubMedPubMedCentral

28.

Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire C, Chen JW, et al. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8(1):483–94. https://doi.org/10.1021/nn404945r.CrossRefPubMedPubMedCentral

29.

Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4(1):26316. https://doi.org/10.3402/jev.v4.26316.CrossRefPubMed

30.

Yang T, Fogarty B, LaForge B, Aziz S, Pham T, Lai L, et al. Delivery of small interfering RNA to inhibit vascular endothelial growth factor in zebrafish using natural brain endothelia cell-secreted exosome nanovesicles for the treatment of brain cancer. AAPS J. 2017;19(2):475–86. https://doi.org/10.1208/s12248-016-0015-y.CrossRefPubMed

31.

Saari H, Lazaro-Ibanez E, Viitala T, Vuorimaa-Laukkanen E, Siljander P, Yliperttula M. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of paclitaxel in autologous prostate cancer cells. J Control Release. 2015;220(Pt B):727–37. https://doi.org/10.1016/j.jconrel.2015.09.031.CrossRefPubMed

32.

Paschon V, Takada SH, Ikebara JM, Sousa E, Raeisossadati R, Ulrich H, et al. Interplay between exosomes, microRNAs and toll-like receptors in brain disorders. Mol Neurobiol. 2016;53(3):2016–28. https://doi.org/10.1007/s12035-015-9142-1.CrossRefPubMed

33.

Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–79. https://doi.org/10.1038/nri855. CrossRefPubMed

34.

Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. 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. https://doi.org/10.1002/stem.1409. CrossRefPubMedPubMedCentral

35.

Sorensen AL, Timoskainen S, West FD, Vekterud K, Boquest AC, Ahrlund-Richter L, et al. Lineage-specific promoter DNA methylation patterns segregate adult progenitor cell types. Stem Cells Dev. 2010;19(8):1257–66. https://doi.org/10.1089/scd.2009.0309.CrossRefPubMed

36.

Klinker MW, Marklein RA, Lo Surdo JL, Wei CH, Bauer SR. Morphological features of IFN-gamma-stimulated mesenchymal stromal cells predict overall immunosuppressive capacity. Proc Natl Acad Sci U S A. 2017;114(13):E2598–E607. https://doi.org/10.1073/pnas.1617933114. CrossRefPubMedPubMedCentral

37.

Grønberg NV, Johansen FF, Kristiansen U, Hasseldam H. Leukocyte infiltration in experimental stroke. J Neuroinflammation. 2013;10:115. https://doi.org/10.1186/1742-2094-10-115. CrossRefPubMedPubMedCentral

38.

Chen Y, Garcia GE, Huang W, Constantini S. The involvement of secondary neuronal damage in the development of neuropsychiatric disorders following brain insults. Front Neurol. 2014;5:22. https://doi.org/10.3389/fneur.2014.00022.PubMedPubMedCentralCrossRef

39.

Prinz M, Erny D, Hagemeyer N. Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol. 2017;18(4):385–92. https://doi.org/10.1038/ni.3703.CrossRefPubMed

40.

Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing [gamma][delta]T cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15(8):946–50. http://www.nature.com/nm/journal/v15/n8/suppinfo/nm.1999_S1.html CrossRefPubMed

41.

Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke. Lancet Neurol. 2010;9(9):895–905. https://doi.org/10.1016/S1474-4422(10)70164-2.CrossRefPubMedPubMedCentral

42.

Lovblad KO, Baird AE, Schlaug G, Benfield A, Siewert B, Voetsch B, et al. Ischemic lesion volumes in acute stroke by diffusion-weighted magnetic resonance imaging correlate with clinical outcome. Ann Neurol. 1997;42(2):164–70. https://doi.org/10.1002/ana.410420206.CrossRefPubMed

43.

Schellinger PD, Jansen O, Fiebach JB, Hacke W, Sartor K. A standardized MRI stroke protocol: comparison with CT in hyperacute intracerebral hemorrhage. Stroke. 1999;30(4):765–8. https://doi.org/10.1161/01.STR.30.4.765.CrossRefPubMed

44.

Otero-Ortega L, Gomez de Frutos MC, Laso-Garcia F, Rodriguez-Frutos B, Medina-Gutierrez E, Lopez JA, et al. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2017; https://doi.org/10.1177/0271678X17708917.

45.

Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1(2):92–100. https://doi.org/10.1016/S1474-4422(02)00040-6.CrossRefPubMed

46.

Yin KJ, Hamblin M, Chen YE. Angiogenesis-regulating microRNAs and ischemic stroke. Curr Vasc Pharmacol. 2015;13(3):352–65. https://doi.org/10.2174/15701611113119990016.CrossRefPubMedPubMedCentral

47.

Teng H, Zhang ZG, Wang L, Zhang RL, Zhang L, Morris D, et al. Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab. 2008;28(4):764–71. https://doi.org/10.1038/sj.jcbfm.9600573.CrossRefPubMed

48.

Zhang Y, Chopp M, Meng Y, Katakowski M, Xin H, Mahmood A, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122(4):856–67. https://doi.org/10.3171/2014.11.JNS14770.CrossRefPubMedPubMedCentral

49.

Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos MD, Rodriguez-Frutos B, Pascual-Guerra J, Fuentes B, et al. White matter repair after extracellular vesicles administration in an experimental animal model of subcortical stroke. Sci Rep. 2017;7:44433. https://doi.org/10.1038/srep44433.CrossRefPubMedPubMedCentral

50.

Charrin S, Jouannet S, Boucheix C, Rubinstein E. Tetraspanins at a glance. J Cell Sci. 2014;127(17):3641–8. https://doi.org/10.1242/jcs.154906.CrossRefPubMed

51.

Schaar KL, Brenneman MM, Savitz SI. Functional assessments in the rodent stroke model. Exp Transl Stroke Med. 2010;2(1):13. https://doi.org/10.1186/2040-7378-2-13.CrossRefPubMedPubMedCentral

52.

Xin H, Wang F, Li Y, QE L, Cheung WL, Zhang Y, et al. Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from microRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant. 2017;26(2):243–57. https://doi.org/10.3727/096368916X693031.CrossRefPubMedPubMedCentral

53.

Blum S, Hebert AE, Dash PK. A role for the prefrontal cortex in recall of recent and remote memories. Neuroreport. 2006;17(3):341–4. https://doi.org/10.1097/01.wnr.0000201509.53750.bc.CrossRefPubMed

54.

Halgren E, Babb TL, Crandall PH. Activity of human hippocampal formation and amygdala neurons during memory testing. Electroencephalogr Clin Neurophysiol. 1978;45(5):585–601. https://doi.org/10.1016/0013-4694(78)90159-1.CrossRefPubMed

55.

Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6(2):119–30. https://doi.org/10.1038/nrn1607.CrossRefPubMed

56.

Lockhart SN, Mayda AB, Roach AE, Fletcher E, Carmichael O, Maillard P, et al. Episodic memory function is associated with multiple measures of white matter integrity in cognitive aging. Front Hum Neurosci. 2012;6:56. https://doi.org/10.3389/fnhum.2012.00056.CrossRefPubMedPubMedCentral

57.

Tulving E, Markowitsch HJ. Episodic and declarative memory: role of the hippocampus. Hippocampus. 1998;8(3):198–204. https://doi.org/10.1002/(SICI)1098-1063(1998)8:3<198::AID-HIPO2>3.0.CO;2-G.CrossRefPubMed

58.

Lundy-Ekman L. Neuroscience : fundamentals for rehabilitation. 4th ed. St. Louis: Elsevier; 2013.

Title: Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model
Authors: Robin L. Webb
Erin E. Kaiser
Shelley L. Scoville
Tyler A. Thompson
Sumbul Fatima
Chirayukumar Pandya
Karishma Sriram
Raymond L. Swetenburg
Kumar Vaibhav
Ali S. Arbab
Babak Baban
Krishnan M. Dhandapani
David C. Hess
M. N. Hoda
Steven L. Stice
Publication date: 01-10-2018
Publisher: Springer US
Published in: Translational Stroke Research / Issue 5/2018
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-017-0599-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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