Статья

Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders

Milad RiazifarEdwards Lifesciences (United States)M. Rezaa MohammadiDepartment of Materials Science and Engineering, University of California, Irvine, Irvine, California 92697, United StatesEgest J. PoneDepartment 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 StatesAshish YeriNeurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United StatesCecilia LässerKrefting Research Center, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, SwedenAude I. SégalinyDepartment 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 StatesLaura L. McIntyreDepartment of Molecular Biology and Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, University of California, Irvine, Irvine, California 92697, United StatesGanesh Vilas ShelkeDepartment of Surgery, Institute of Clinical Sciences, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg 41345, SwedenElizabeth HutchinsNeurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United StatesAshley HamamotoDepartment 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 StatesErika N. CalleDepartment 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 StatesRossella CrescitelliKrefting Research Center, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, SwedenWenbin LiaoDepartment 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 StatesVictor PhamDepartment 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 StatesYanan YinDepartment of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaJayapriya JayaramanDepartment 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 StatesJonathan R. T. LakeyDepartment of Surgery, University of California, Irvine, Orange, California 92868, United StatesCraig M. WalshDepartment of Molecular Biology and Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, University of California, Irvine, Irvine, California 92697, United StatesKendall Van Keuren‐JensenNeurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona 85004, United StatesJan LötvallKrefting Research Center, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, SwedenWeian ZhaoDepartment 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

2019en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1021/acsnano.9b01004

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar