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

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

doi:10.1007/s12975-017-0599-2

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

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

Research output: Contribution to journal › Article › peer-review

174 Scopus citations

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.

Original language	English
Pages (from-to)	530-539
Number of pages	10
Journal	Translational Stroke Research
Volume	9
Issue number	5
DOIs	https://doi.org/10.1007/s12975-017-0599-2
State	Published - Oct 1 2018

Bibliographical note

Funding Information:
The authors would like to thank Caroline Jackson, Justin Sharma, Austin Passaro, and Viviana Martinez who were involved with various aspects of the EV manufacturing process and figure preparation. We would also like to thank Tracey Stice for the project management guidance as well as Beth Richardson and Mary Ard at the University of Georgia Electron Microscopy Core for their technical assistance and expertise. R.L.W. and S.L.S. have submitted a patent filing on the NSC EVs, and this technology is licensed from the UGA Research Foundation by ArunA Biomedical, Inc. R.L.W., S.L.S., T.A.T., R.L.S., and S.L.S. are affiliated with ArunA Biomedical, Inc. and own equity in the company.

Funding Information:
Funding This work was supported by ArunA Biomedical, Inc., and R.L.S. was partially supported by the Science and Technology Center Emergent Behaviors of Integrated Cellular Systems (EBICS) Grant No. CBET-0939511.

Publisher Copyright:
© 2017, The Author(s).

Keywords

Neural stem cell extracellular vesicles
Preclinical stroke model
Thromboembolic stroke

ASJC Scopus subject areas

Neuroscience (all)
Clinical Neurology
Cardiology and Cardiovascular Medicine

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10.1007/s12975-017-0599-2

Cite this

Webb, R. L., Kaiser, E. E., Scoville, S. L., Thompson, T. A., Fatima, S., Pandya, C., Sriram, K., Swetenburg, R. L., Vaibhav, K., Arbab, A. S., Baban, B., Dhandapani, K. M., Hess, D. C., Hoda, M. N., & Stice, S. L. (2018). Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. Translational Stroke Research, 9(5), 530-539. https://doi.org/10.1007/s12975-017-0599-2

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

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.",

keywords = "Neural stem cell extracellular vesicles, Preclinical stroke model, Thromboembolic stroke",

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

note = "Funding Information: The authors would like to thank Caroline Jackson, Justin Sharma, Austin Passaro, and Viviana Martinez who were involved with various aspects of the EV manufacturing process and figure preparation. We would also like to thank Tracey Stice for the project management guidance as well as Beth Richardson and Mary Ard at the University of Georgia Electron Microscopy Core for their technical assistance and expertise. R.L.W. and S.L.S. have submitted a patent filing on the NSC EVs, and this technology is licensed from the UGA Research Foundation by ArunA Biomedical, Inc. R.L.W., S.L.S., T.A.T., R.L.S., and S.L.S. are affiliated with ArunA Biomedical, Inc. and own equity in the company. Funding Information: Funding This work was supported by ArunA Biomedical, Inc., and R.L.S. was partially supported by the Science and Technology Center Emergent Behaviors of Integrated Cellular Systems (EBICS) Grant No. CBET-0939511. Publisher Copyright: {\textcopyright} 2017, The Author(s).",

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Webb, RL, Kaiser, EE, Scoville, SL, Thompson, TA, Fatima, S, Pandya, C, Sriram, K, Swetenburg, RL, Vaibhav, K, Arbab, AS, Baban, B, Dhandapani, KM, Hess, DC, Hoda, MN & Stice, SL 2018, 'Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model', Translational Stroke Research, vol. 9, no. 5, pp. 530-539. https://doi.org/10.1007/s12975-017-0599-2

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T1 - Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model

AU - Webb, Robin L.

AU - Kaiser, Erin E.

AU - Scoville, Shelley L.

AU - Thompson, Tyler A.

AU - Fatima, Sumbul

AU - Pandya, Chirayukumar

AU - Sriram, Karishma

AU - Swetenburg, Raymond L.

AU - Vaibhav, Kumar

AU - Arbab, Ali S.

AU - Baban, Babak

AU - Dhandapani, Krishnan M.

AU - Hess, David C.

AU - Hoda, M. N.

AU - Stice, Steven L.

N1 - Funding Information: The authors would like to thank Caroline Jackson, Justin Sharma, Austin Passaro, and Viviana Martinez who were involved with various aspects of the EV manufacturing process and figure preparation. We would also like to thank Tracey Stice for the project management guidance as well as Beth Richardson and Mary Ard at the University of Georgia Electron Microscopy Core for their technical assistance and expertise. R.L.W. and S.L.S. have submitted a patent filing on the NSC EVs, and this technology is licensed from the UGA Research Foundation by ArunA Biomedical, Inc. R.L.W., S.L.S., T.A.T., R.L.S., and S.L.S. are affiliated with ArunA Biomedical, Inc. and own equity in the company. Funding Information: Funding This work was supported by ArunA Biomedical, Inc., and R.L.S. was partially supported by the Science and Technology Center Emergent Behaviors of Integrated Cellular Systems (EBICS) Grant No. CBET-0939511. Publisher Copyright: © 2017, The Author(s).

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N2 - 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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KW - Preclinical stroke model

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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