دورية أكاديمية
Neural stem cells traffic functional mitochondria via extracellular vesicles.
العنوان: | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
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المؤلفون: | Peruzzotti-Jametti L; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Bernstock JD; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.; National Institutes of Health (NINDS/NIH), Bethesda, Maryland, United States of America., Willis CM; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Manferrari G; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Rogall R; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Fernandez-Vizarra E; MRC Mitochondrial Biology Unit, University of Cambridge, United Kingdom., Williamson JC; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom.; NHS Blood and Transplant, Cambridge, United Kingdom., Braga A; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., van den Bosch A; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Leonardi T; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.; Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan, Italy., Krzak G; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Kittel Á; Institute of Experimental Medicine, Eötvös Lorand Research Network, Budapest, Hungary., Benincá C; MRC Mitochondrial Biology Unit, University of Cambridge, United Kingdom., Vicario N; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.; Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Italy., Tan S; UMR-CBMN CNRS-Université de Bordeaux-IPB, France., Bastos C; Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom., Bicci I; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom., Iraci N; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.; Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Italy., Smith JA; Cambridge Innovation Technologies Consulting (CITC) Limited, United Kingdom., Peacock B; NanoFCM Co., Ltd, Nottingham, United Kingdom., Muller KH; Cambridge Advanced Imaging Centre (CAIC), United Kingdom., Lehner PJ; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom.; NHS Blood and Transplant, Cambridge, United Kingdom., Buzas EI; Semmelweis University, Budapest, Hungary.; HCEMM Kft HU, Budapest, Hungary.; ELKH-SE, Budapest, Hungary., Faria N; Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom., Zeviani M; MRC Mitochondrial Biology Unit, University of Cambridge, United Kingdom., Frezza C; MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge United Kingdom., Brisson A; UMR-CBMN CNRS-Université de Bordeaux-IPB, France., Matheson NJ; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom.; NHS Blood and Transplant, Cambridge, United Kingdom.; Department of Medicine, University of Cambridge, United Kingdom., Viscomi C; MRC Mitochondrial Biology Unit, University of Cambridge, United Kingdom., Pluchino S; Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, United Kingdom.; Cambridge Innovation Technologies Consulting (CITC) Limited, United Kingdom. |
المصدر: | PLoS biology [PLoS Biol] 2021 Apr 07; Vol. 19 (4), pp. e3001166. Date of Electronic Publication: 2021 Apr 07 (Print Publication: 2021). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: San Francisco, CA : Public Library of Science, [2003]- |
مواضيع طبية MeSH: | Extracellular Vesicles/*metabolism , Mitochondria/*metabolism , Neural Stem Cells/*metabolism, Animals ; Biological Transport ; Cells, Cultured ; Female ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neural Stem Cells/ultrastructure |
مستخلص: | Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases. Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SP is co-founder, CSO and shareholder (>5%) of CITC Ltd. and iSTEM Therapeutics Litd., and co-founder and Non-executive Director at asitia Therapeutics Ltd.; LPJ is shareholder of CITC Ltd.; JAS is a Project Manager and Senior Research Associate at CITC Ltd. and Director of Research of iSTEM Therapeutics Ltd.; BP is an employee of NanoFCM and his contributions to this paper were made as part of their employment. |
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معلومات مُعتمدة: | MC_EX_MR/P007031/1 United Kingdom MRC_ Medical Research Council; 210688/Z/18/Z United Kingdom WT_ Wellcome Trust; MR/V011561/1 United Kingdom MRC_ Medical Research Council; MRF_MRF-175-0001-RG-ZEVI-C0898 United Kingdom MRF MRF; MC_UU_12022/6 United Kingdom MRC_ Medical Research Council; MC_UU_00015/5 United Kingdom MRC_ Medical Research Council; MC_UU_00015/8 United Kingdom MRC_ Medical Research Council; MC_UP_1101/3 United Kingdom MRC_ Medical Research Council; RRZA/057 RG79423 United Kingdom WT_ Wellcome Trust; MR/K026682/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; United Kingdom WT_ Wellcome Trust; MC_UP_1002/1 United Kingdom MRC_ Medical Research Council; 101835/Z/13/Z United Kingdom WT_ Wellcome Trust; RRAG/214 United Kingdom WT_ Wellcome Trust; MR/P008801/1 United Kingdom MRC_ Medical Research Council; United Kingdom DH_ Department of Health; MRF_MRF-155-0002-RG-ZEVIA United Kingdom MRF MRF |
المشرفين على المادة: | 147336-22-9 (Green Fluorescent Proteins) |
تواريخ الأحداث: | Date Created: 20210407 Date Completed: 20210824 Latest Revision: 20240717 |
رمز التحديث: | 20240717 |
مُعرف محوري في PubMed: | PMC8055036 |
DOI: | 10.1371/journal.pbio.3001166 |
PMID: | 33826607 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1545-7885 |
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DOI: | 10.1371/journal.pbio.3001166 |