Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

Shaowei Guo; Nisim Perets; Oshra Betzer; Shahar Ben-Shaul; Anton Sheinin; Izhak Michaelevski; Rachela Popovtzer; Daniel Offen; Shulamit Levenberg

doi:10.1021/acsnano.9b01892

Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

Shaowei Guo, Nisim Perets, Oshra Betzer, Shahar Ben-Shaul, Anton Sheinin, Izhak Michaelevski, Rachela Popovtzer, Daniel Offen, Shulamit Levenberg

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

344 Scopus citations

Abstract

Individuals with spinal cord injury (SCI) usually suffer from permanent neurological deficits, while spontaneous recovery and therapeutic efficacy are limited. Here, we demonstrate that when given intranasally, exosomes derived from mesenchymal stem cells (MSC-Exo) could pass the blood brain barrier and migrate to the injured spinal cord area. Furthermore, MSC-Exo loaded with phosphatase and tensin homolog small interfering RNA (ExoPTEN) could attenuate the expression of PTEN in the injured spinal cord region following intranasal administrations. In addition, the loaded MSC-Exo considerably enhanced axonal growth and neovascularization, while reducing microgliosis and astrogliosis. The intranasal ExoPTEN therapy could also partly improve structural and electrophysiological function and, most importantly, significantly elicited functional recovery in rats with complete SCI. The results imply that intranasal ExoPTEN may be used clinically to promote recovery for SCI individuals.

Original language	English
Pages (from-to)	10015-10028
Number of pages	14
Journal	ACS Nano
Volume	13
Issue number	9
DOIs	https://doi.org/10.1021/acsnano.9b01892
State	Published - 24 Sep 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

Funding

This work was supported by the J&J Shervington Fund (SL), the Israel Foundation for Spinal Cord Injury (SL), and the Israel Science Foundation ISF 749/14. We would like to thank the Brainboost project for supporting N.P. with a scholarship. We would like to thank the Council for Higher Education and the Ministry of Science, Technology & Space Israel, for supporting O.B. with scholarships. We wish to thank the Technion’s Preclinical Research Authority and M. Tendler for their professional animal care. We thank the Technion’s BCF MRI team. We thank A. Yvgi and S. Finkel for BBB scoring. We also thank J. Zavin for the cryosections, S. Landau for writing the MATLAB code, N. Cohen and T. Bronshtein for the Nanosight assistance, M. Poley and J. Shainsky for the ICP test, and Dr. Y. Posen for proofreading the article.

Funders	Funder number
Israel Foundation
J&J Shervington Fund
Ministry of Science, Technology & Space Israel
Israel Science Foundation	ISF 749/14
Council for Higher Education

Keywords

PTEN siRNA
complete spinal cord injury
exosome
functional recovery
intranasal
targeted delivery

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10.1021/acsnano.9b01892

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title = "Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury",

abstract = "Individuals with spinal cord injury (SCI) usually suffer from permanent neurological deficits, while spontaneous recovery and therapeutic efficacy are limited. Here, we demonstrate that when given intranasally, exosomes derived from mesenchymal stem cells (MSC-Exo) could pass the blood brain barrier and migrate to the injured spinal cord area. Furthermore, MSC-Exo loaded with phosphatase and tensin homolog small interfering RNA (ExoPTEN) could attenuate the expression of PTEN in the injured spinal cord region following intranasal administrations. In addition, the loaded MSC-Exo considerably enhanced axonal growth and neovascularization, while reducing microgliosis and astrogliosis. The intranasal ExoPTEN therapy could also partly improve structural and electrophysiological function and, most importantly, significantly elicited functional recovery in rats with complete SCI. The results imply that intranasal ExoPTEN may be used clinically to promote recovery for SCI individuals.",

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Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury

Abstract

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Keywords

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