Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders
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To dissect therapeutic mechanisms of transplanted stem cells and develop exosome-based nanotherapeutics in treating autoimmune and neurodegenerative diseases, we assessed the effect of exosomes secreted from human mesenchymal stem cells (MSCs) in treating multiple sclerosis using an experimental autoimmune encephalomyelitis (EAE) mouse model. We found that intravenous administration of exosomes produced by MSCs stimulated by IFNγ (IFNγ-Exo) (i) reduced the mean clinical score of EAE mice compared to PBS control, (ii) reduced demyelination, (iii) decreased neuroinflammation, and (iv) upregulated the number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords of EAE mice. Co-culture of IFNγ-Exo with activated peripheral blood mononuclear cells (PBMCs) cells in vitro reduced PBMC proliferation and levels of pro-inflammatory Th1 and Th17 cytokines including IL-6, IL-12p70, IL-17AF, and IL-22 yet increased levels of immunosuppressive cytokine indoleamine 2,3-dioxygenase. IFNγ-Exo could also induce Tregs in vitro in a murine splenocyte culture, likely mediated by a third-party accessory cell type. Further, IFNγ-Exo characterization by deep RNA sequencing suggested that IFNγ-Exo contains anti-inflammatory RNAs, where their inactivation partially hindered the exosomes potential to induce Tregs. Furthermore, we found that IFNγ-Exo harbors multiple anti-inflammatory and neuroprotective proteins. These results not only shed light on stem cell therapeutic mechanisms but also provide evidence that MSC-derived exosomes can potentially serve as cell-free therapies in creating a tolerogenic immune response to treat autoimmune and central nervous system disorders.
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Exosome-stimulated MSCs produced by γ-interferon have significant effects in the treatment of autoimmune encephalomyelitis.
“Riazifar et al. showed that exosome-stimulated MSCs produced by γ-interferon have been shown to have significant effects in the treatment of autoimmune encephalomyelitis (EAE) [78].”
From The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System (2022) · cites this paper as [78]
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- Authors
- Riazifar, M., Mohammadi, M. R., Pone, E. J., Yeri, A., Lässer, C., Segaliny, A. I., McIntyre, L. L., Shelke, G. V., Hutchins, E., Hamamoto, A., Calle, E. N., Crescitelli, R., Liao, W., Pham, V., Yin, Y., Jayaraman, J., Lakey, J. R. T., Walsh, C. M., Van Keuren-Jensen, K., Lotvall, J., & Zhao, W.
- Affiliations
- University of California, Irvine (US)
- Translational Genomics Research Institute (US)
- University of Gothenburg (SE)
- Department of Pharmaceutical Sciences, Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center, Edwards Life Sciences Center for Advanced Cardiovascular Technology, Department of Biomedical Engineering, and Department of Biological Chemistry, University of California, Irvine, Irvine, California 92697, United States
- Sahlgrenska University Hospital (SE)
- Shanghai Jiao Tong University (CN)
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United States
- Krefting Research Center, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden
- Corresponding author
- Zhao, Weian
- ORCID
- Venue
- ACS Nano
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-05-22
- Volume
- 13
- Issue
- 6
- Pages
- 6670-6688
- ISSN
- 1936-0851 (ISSN-L)
- 1936-086X
- PMC
- PMC6880946
- OpenAlex
- W2944971749
- Cited by
- 551
- References
- 99
- Citations by year
- 2026: 47 · 2025: 62 · 2024: 94 · 2023: 87 · 2022: 96 · 2021: 90 · 2020: 64 · 2019: 11
- FWCI
- 21.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Nano (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (1DP2CA195763-01)
- Fondation ARC pour la Recherche sur le Cancer (SAE20150602901)
- University of California, Irvine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- stem cell-derived exosomes, mesenchymal stem cells, nanotherapeutics, multiple sclerosis, experimental autoimmune encephalomyelitis, regulatory T cells, demyelination, neuroinflammation, Th17 cytokines, indoleamine 2,3-dioxygenase, anti-inflammatory microRNA, cell-free therapy, neuroprotection, neurodegenerative diseases, autoimmune disease
- MeSH terms
- Animals, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental, Female, Humans, Interferon-gamma, Interleukins, Male, Mice, Inbred C57BL, Monocytes, Mesenchymal Stem Cell Transplantation, T-Lymphocytes, Regulatory, Mice, Exosomes, Mesenchymal Stem Cells
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