Publication date: May 22, 2019
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 PBMC cells in vitro reduced PBMC proliferation and levels of proinflammatory Th1 and Th17 cytokines including IL-6, IL-12p70, IL-17AF, and IL-22 yet increased level of immunosuppressive cytokine indoleamine 2,3-dioxygenase (IDO). IFNγ-Exo could also induce Tregs in vitro in murine splenocyte culture, likely mediated by a third-party accessory cell type. Further IFNγ-Exo characterization by deep RNA sequencing suggested that IFNγ-Exo contain 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 mechanism, 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.
Riazifar, M., Mohammadi, Pone, E.J., Yeri, A., L”asser, C., Segaliny, A.I., McIntyre, L.L., Shelke, G.V., Hutchins, E., Hamamoto, A., Calle, E.N., Crescitelli, R., Liao, W., , Pham, Yin, Y., Jayaraman, J., , Lakey, Walsh, C.M., Van Keuren-Jensen, K., Lotvall, J., and Zhao, W. Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders. 18091. 2019 ACS Nano.
|disease||MESH||central nervous system disorders|
|disease||MESH||experimental autoimmune encephalomyelitis|
|drug||DRUGBANK||Mesenchymal Stem Cells|