Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema
Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been...
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Frontiers Media S.A.
2021-05-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.661385/full |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Mariana A. Antunes Mariana A. Antunes Cassia L. Braga Tainá B. Oliveira Jamil Z. Kitoko Jamil Z. Kitoko Ligia L. Castro Ligia L. Castro Debora G. Xisto Mariana S. Coelho Nazareth Rocha Nazareth Rocha Rodrigo P. Silva-Aguiar Celso Caruso-Neves Eduarda G. Martins Clara Fernandes Carvalho Antônio Galina Daniel J. Weiss José R. Lapa e Silva Miquéias Lopes-Pacheco Miquéias Lopes-Pacheco Fernanda F. Cruz Fernanda F. Cruz Patricia R. M. Rocco Patricia R. M. Rocco |
spellingShingle |
Mariana A. Antunes Mariana A. Antunes Cassia L. Braga Tainá B. Oliveira Jamil Z. Kitoko Jamil Z. Kitoko Ligia L. Castro Ligia L. Castro Debora G. Xisto Mariana S. Coelho Nazareth Rocha Nazareth Rocha Rodrigo P. Silva-Aguiar Celso Caruso-Neves Eduarda G. Martins Clara Fernandes Carvalho Antônio Galina Daniel J. Weiss José R. Lapa e Silva Miquéias Lopes-Pacheco Miquéias Lopes-Pacheco Fernanda F. Cruz Fernanda F. Cruz Patricia R. M. Rocco Patricia R. M. Rocco Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema Frontiers in Cell and Developmental Biology cell therapy COPD mesenchymal stromal cells extracellular vesicles inflammation macrophages |
author_facet |
Mariana A. Antunes Mariana A. Antunes Cassia L. Braga Tainá B. Oliveira Jamil Z. Kitoko Jamil Z. Kitoko Ligia L. Castro Ligia L. Castro Debora G. Xisto Mariana S. Coelho Nazareth Rocha Nazareth Rocha Rodrigo P. Silva-Aguiar Celso Caruso-Neves Eduarda G. Martins Clara Fernandes Carvalho Antônio Galina Daniel J. Weiss José R. Lapa e Silva Miquéias Lopes-Pacheco Miquéias Lopes-Pacheco Fernanda F. Cruz Fernanda F. Cruz Patricia R. M. Rocco Patricia R. M. Rocco |
author_sort |
Mariana A. Antunes |
title |
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema |
title_short |
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema |
title_full |
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema |
title_fullStr |
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema |
title_full_unstemmed |
Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema |
title_sort |
mesenchymal stromal cells from emphysematous donors and their extracellular vesicles are unable to reverse cardiorespiratory dysfunction in experimental severe emphysema |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2021-05-01 |
description |
Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema. |
topic |
cell therapy COPD mesenchymal stromal cells extracellular vesicles inflammation macrophages |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.661385/full |
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doaj-8bef1ff43cb042c6abe44a3fba9bb1cc2021-05-31T15:02:27ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-05-01910.3389/fcell.2021.661385661385Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe EmphysemaMariana A. Antunes0Mariana A. Antunes1Cassia L. Braga2Tainá B. Oliveira3Jamil Z. Kitoko4Jamil Z. Kitoko5Ligia L. Castro6Ligia L. Castro7Debora G. Xisto8Mariana S. Coelho9Nazareth Rocha10Nazareth Rocha11Rodrigo P. Silva-Aguiar12Celso Caruso-Neves13Eduarda G. Martins14Clara Fernandes Carvalho15Antônio Galina16Daniel J. Weiss17José R. Lapa e Silva18Miquéias Lopes-Pacheco19Miquéias Lopes-Pacheco20Fernanda F. Cruz21Fernanda F. Cruz22Patricia R. M. Rocco23Patricia R. M. Rocco24Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Inflammation and Immunity, Paulo Goes Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilDepartment of Physiology and Pharmacology, Fluminense Federal University, Niterói, BrazilLaboratory of Biochemistry and Cell Signaling, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Biochemistry and Cell Signaling, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLeopoldo De Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLeopoldo De Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLeopoldo De Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilDepartment of Medicine, College of Medicine, University of Vermont, Burlington, VT, United StatesInstitute of Thoracic Medicine, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilAlthough bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-β, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1β and TGF-β levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.https://www.frontiersin.org/articles/10.3389/fcell.2021.661385/fullcell therapyCOPDmesenchymal stromal cellsextracellular vesiclesinflammationmacrophages |