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Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity

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Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and a leading cause of dementia. Although the amyloid-β (Aβ) peptide is deemed a crucial driver of AD, there are no effective therapeutics available to treat Aβ-caused neurotoxicity. Extracellular vesicles (EVs) are membrane-bound small particles mediating intercellular traffic of nucleic acids, lipids, proteins, and metabolites. Exosomes are a subtype of EVs with a size range of 30–150 nm in diameter. Stem cell-derived EVs are a potential therapeutic for AD, while EVs isolated from normal stem cell cultures generally have a low yield. Here, we studied the EVs secreted by the rat neural stem cells in the presence of heat shock (HS) stimulus. Nanoparticle tracking analysis confirmed that HS-derived EVs exhibit significantly higher concentration and larger diameter in comparison to the non-heat shock (NHS)-derived EVs. Mass spectrometric studies of EV proteins revealed that HS-derived EVs contained fewer diverse proteins than NHS-derived exosomes. GO enrichment analysis of the proteins suggested that the top two biological functions of the proteins in HS-derived EVs are involved in the negative regulation of apoptotic process and positive modulation of DNA repair. Importantly, the therapeutic efficacy of the NHS- and HS-derived EVs were tested in a cell culture model of AD: HS-derived EVs exhibited greater neuroprotection against not only oxidative stress but also amyloid-β (Aβ) induced neurotoxicity compared to NHS-derived EVs. Moreover, HS-derived EVs were also able to dramatically attenuate Aβ-induced apoptosis and oxidative stress. These data indicate that in response to HS, neural stem cells increase EV production and alter EV morphology and cargo to confer better neuroprotection against oxidative stress and Aβ-caused neurotoxicity, suggesting that HS-induced EVs from neural stem cells can be a therapeutic agent for AD and possibly other neurological disorders.

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Data Availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Dr. Aravind Baride in the Department of Chemistry at the University of South Dakota for his assistance in electron microscopy.

Funding

This work was supported in part by the National Science Foundation (NSF) (DGE-1633213), NIH/NIGMS (T32GM-136503), NIH/NIGMS P20 GM103443-20, and NIH/NIA RF1 AG072510. Any opinions, findings, conclusions, or recommendations expressed in this material are those from the authors and do not necessarily reflect the views from the NSF or NIH.

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Authors and Affiliations

  1. Division of Basic Biomedical Sciences and Center for Brain and Behavior Research, Sanford School of Medicine, University of South Dakota, Vermillion, SD, 57069, USA

    Christa C. Huber, Eduardo A. Callegari, Maria D. Paez & Hongmin Wang

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA

    Svetlana Romanova

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  1. Christa C. Huber
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  2. Eduardo A. Callegari
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  3. Maria D. Paez
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  4. Svetlana Romanova
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  5. Hongmin Wang
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Contributions

Christa C. Huber and Hongmin Wang contributed to the study conception and design. Experiments and data analysis were performed by Christa C. Huber, Eduardo A. Callegari, Maria D. Paez, Svetlana Romanova and Hongmin Wang. The first draft of the manuscript was written by Christa C. Huber. All authors read and approved the final manuscript.

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Correspondence to Hongmin Wang.

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Huber, C.C., Callegari, E.A., Paez, M.D. et al. Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity. Mol Neurobiol 59, 7404–7412 (2022). https://doi.org/10.1007/s12035-022-03055-3

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