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

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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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Most cited references 38

Record: found
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Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.

Charles P. Lai, Osama Mardini, Maria Ericsson … (2014)

Extracellular vesicles (EVs) are nanosized vesicles released by normal and diseased cells as a novel form of intercellular communication and can serve as an effective therapeutic vehicle for genes and drugs. Yet, much remains unknown about the in vivo properties of EVs such as tissue distribution, blood levels, and urine clearance, important parameters that will define their therapeutic effectiveness and potential toxicity. Here we combined Gaussia luciferase and metabolic biotinylation to create a sensitive EV reporter (EV-GlucB) for multimodal imaging in vivo, as well as monitoring of EV levels in the organs and biofluids ex vivo after administration of EVs. Bioluminescence and fluorescence-mediated tomography imaging on mice displayed a predominant localization of intravenously administered EVs in the spleen followed by the liver. Monitoring EV signal in the organs, blood, and urine further revealed that the EVs first undergo a rapid distribution phase followed by a longer elimination phase via hepatic and renal routes within six hours, which are both faster than previously reported using dye-labeled EVs. Moreover, we demonstrate systemically injected EVs can be delivered to tumor sites within an hour following injection. Altogether, we show the EVs are dynamically processed in vivo with accurate spatiotemporal resolution and target a number of normal organs as well as tumors with implications for disease pathology and therapeutic design.

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Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.

Takashi Shichita, Yuki Sugiyama, Hiroaki Ooboshi … (2009)

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

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Episodic and declarative memory: role of the hippocampus.

E Tulving, H J Markowitsch (1998)

The fact that medial temporal lobe structures, including the hippocampus, are critical for declarative memory is firmly established by now. The understanding of the role that these structures play in declarative memory, however, despite great efforts spent in the quest, has eluded investigators so far. Given the existing scenario, novel ideas that hold the promise of clarifying matters should be eagerly sought. One such idea was recently proposed by Vargha-Khadem and her colleagues (Science 1997; 277:376-380) on the basis of their study of three young people suffering from anterograde amnesia caused by early-onset hippocampal pathology. The idea is that the hippocampus is necessary for remembering ongoing life's experiences (episodic memory), but not necessary for the acquisition of factual knowledge (semantic memory). We discuss the reasons why this novel proposal makes good sense and why it and its ramifications should be vigorously pursued. We review and compare declarative and episodic theories of amnesia, and argue that the findings reported by Vargha-Khadem and her colleagues fit well into an episodic theory that retains components already publicized, and adds new ones suggested by the Vargha-Khadem et al. study. Existing components of this theory include the idea that acquisition of factual knowledge can occur independently of episodic memory, and the idea that in anterograde amnesia it is quite possible for episodic memory to be more severely impaired than semantic memory. We suggest a realignment of organization of memory such that declarative memory is defined in terms of features and properties that are common to both episodic and semantic memory. The organization of memory thus modified gives greater precision to the Vargha-Khadem et al. neuroanatomical model in which declarative memory depends on perihippocampal cortical regions but not on the hippocampus, whereas episodic memory, which is separate from declarative memory, depends on the hippocampus.

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Author and article information

Contributors

Steven L. Stice: sstice@arunabiomedical.com

Journal

Journal ID (nlm-ta): Transl Stroke Res

Journal ID (iso-abbrev): Transl Stroke Res

Title: Translational Stroke Research

Publisher: Springer US (New York )

ISSN (Print): 1868-4483

ISSN (Electronic): 1868-601X

Publication date (Electronic): 28 December 2017

Publication date PMC-release: 28 December 2017

Publication date (Print): 2018

Volume: 9

Issue: 5

Pages: 530-539

Affiliations

[1 ]GRID grid.432229.c, ArunA Biomedical, ; Athens, GA 30602 USA

[2 ]ISNI 0000 0004 1936 738X, GRID grid.213876.9, Regenerative Bioscience Center, Rhodes Center for Animal and Dairy Science, , University of Georgia, ; Athens, GA 30602 USA

[3 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Medical Laboratory, Imaging, and Radiologic Sciences, , Augusta University, ; Augusta, GA 30912 USA

[4 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Cancer Center, , Augusta University, ; Augusta, GA 30912 USA

[5 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Oral Biology, Dental College of Georgia, , Augusta University, ; Augusta, GA 30912 USA

[6 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Neurosurgery, , Augusta University, ; Augusta, GA 30912 USA

[7 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Department of Neurology, , Augusta University, ; Augusta, GA 30912 USA

Article

Publisher ID: 599

DOI: 10.1007/s12975-017-0599-2

PMC ID: 6132936

PubMed ID: 29285679

SO-VID: e049b154-1985-4423-9045-2fed681501a6

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 9 November 2017

Date revision received : 12 December 2017

Date accepted : 14 December 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100008982, National Science Foundation;

Award ID: CBET-0939511

Award Recipient : Steven L. Stice

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: neural stem cell extracellular vesicles,thromboembolic stroke,preclinical stroke model

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: neural stem cell extracellular vesicles, thromboembolic stroke, preclinical stroke model

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

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Abstract

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Bacterial extracellular vesicles

Most cited references 38

Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.

Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.

Episodic and declarative memory: role of the hippocampus.

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