Neural stem cells traffic functional mitochondria via extracellular vesicles.
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 mec...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-04-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001166&type=printable |
| _version_ | 1826554811642806272 |
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| author | Luca Peruzzotti-Jametti Joshua D Bernstock Cory M Willis Giulia Manferrari Rebecca Rogall Erika Fernandez-Vizarra James C Williamson Alice Braga Aletta van den Bosch Tommaso Leonardi Grzegorz Krzak Ágnes Kittel Cristiane Benincá Nunzio Vicario Sisareuth Tan Carlos Bastos Iacopo Bicci Nunzio Iraci Jayden A Smith Ben Peacock Karin H Muller Paul J Lehner Edit Iren Buzas Nuno Faria Massimo Zeviani Christian Frezza Alain Brisson Nicholas J Matheson Carlo Viscomi Stefano Pluchino |
| author_facet | Luca Peruzzotti-Jametti Joshua D Bernstock Cory M Willis Giulia Manferrari Rebecca Rogall Erika Fernandez-Vizarra James C Williamson Alice Braga Aletta van den Bosch Tommaso Leonardi Grzegorz Krzak Ágnes Kittel Cristiane Benincá Nunzio Vicario Sisareuth Tan Carlos Bastos Iacopo Bicci Nunzio Iraci Jayden A Smith Ben Peacock Karin H Muller Paul J Lehner Edit Iren Buzas Nuno Faria Massimo Zeviani Christian Frezza Alain Brisson Nicholas J Matheson Carlo Viscomi Stefano Pluchino |
| author_sort | Luca Peruzzotti-Jametti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T23:42:41Z |
| format | Article |
| id | doaj.art-62e32062ab904101a16fc0e8ef20d45c |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2025-03-14T07:46:51Z |
| publishDate | 2021-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-62e32062ab904101a16fc0e8ef20d45c2025-03-03T05:30:52ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-04-01194e300116610.1371/journal.pbio.3001166Neural stem cells traffic functional mitochondria via extracellular vesicles.Luca Peruzzotti-JamettiJoshua D BernstockCory M WillisGiulia ManferrariRebecca RogallErika Fernandez-VizarraJames C WilliamsonAlice BragaAletta van den BoschTommaso LeonardiGrzegorz KrzakÁgnes KittelCristiane BenincáNunzio VicarioSisareuth TanCarlos BastosIacopo BicciNunzio IraciJayden A SmithBen PeacockKarin H MullerPaul J LehnerEdit Iren BuzasNuno FariaMassimo ZevianiChristian FrezzaAlain BrissonNicholas J MathesonCarlo ViscomiStefano PluchinoNeural 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.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001166&type=printable |
| spellingShingle | Luca Peruzzotti-Jametti Joshua D Bernstock Cory M Willis Giulia Manferrari Rebecca Rogall Erika Fernandez-Vizarra James C Williamson Alice Braga Aletta van den Bosch Tommaso Leonardi Grzegorz Krzak Ágnes Kittel Cristiane Benincá Nunzio Vicario Sisareuth Tan Carlos Bastos Iacopo Bicci Nunzio Iraci Jayden A Smith Ben Peacock Karin H Muller Paul J Lehner Edit Iren Buzas Nuno Faria Massimo Zeviani Christian Frezza Alain Brisson Nicholas J Matheson Carlo Viscomi Stefano Pluchino Neural stem cells traffic functional mitochondria via extracellular vesicles. PLoS Biology |
| title | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
| title_full | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
| title_fullStr | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
| title_full_unstemmed | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
| title_short | Neural stem cells traffic functional mitochondria via extracellular vesicles. |
| title_sort | neural stem cells traffic functional mitochondria via extracellular vesicles |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3001166&type=printable |
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