Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension
Abstract Background Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanism...
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| Format: | Article |
| Language: | English |
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BMC
2017-10-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13287-017-0669-0 |
| _version_ | 1818289151237160960 |
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| author | Lucas de Mendonça Nathane S. Felix Natália G. Blanco Jaqueline S. Da Silva Tatiana P. Ferreira Soraia C. Abreu Fernanda F. Cruz Nazareth Rocha Patrícia M. Silva Vanessa Martins Vera L. Capelozzi Gizele Zapata-Sudo Patricia R. M. Rocco Pedro L. Silva |
| author_facet | Lucas de Mendonça Nathane S. Felix Natália G. Blanco Jaqueline S. Da Silva Tatiana P. Ferreira Soraia C. Abreu Fernanda F. Cruz Nazareth Rocha Patrícia M. Silva Vanessa Martins Vera L. Capelozzi Gizele Zapata-Sudo Patricia R. M. Rocco Pedro L. Silva |
| author_sort | Lucas de Mendonça |
| collection | DOAJ |
| description | Abstract Background Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Methods Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial–mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68+ and CD163+ macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. Results In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68+ macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial–mesenchymal transition. Conclusion In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype. |
| first_indexed | 2024-12-13T02:07:43Z |
| format | Article |
| id | doaj.art-52617df8e326440b858af42cfb2fd987 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-13T02:07:43Z |
| publishDate | 2017-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-52617df8e326440b858af42cfb2fd9872022-12-22T00:03:05ZengBMCStem Cell Research & Therapy1757-65122017-10-018111510.1186/s13287-017-0669-0Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertensionLucas de Mendonça0Nathane S. Felix1Natália G. Blanco2Jaqueline S. Da Silva3Tatiana P. Ferreira4Soraia C. Abreu5Fernanda F. Cruz6Nazareth Rocha7Patrícia M. Silva8Vanessa Martins9Vera L. Capelozzi10Gizele Zapata-Sudo11Patricia R. M. Rocco12Pedro L. Silva13Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Cardiovascular Pharmacology, Federal University of Rio de JaneiroLaboratory of Inflammation, Oswaldo Cruz Institute—Oswaldo Cruz FoundationLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Inflammation, Oswaldo Cruz Institute—Oswaldo Cruz FoundationLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Histomorphometry and Lung Genomics, University of São Paulo Faculty of MedicineLaboratory of Cardiovascular Pharmacology, Federal University of Rio de JaneiroLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeLaboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Centro de Ciências da SaúdeAbstract Background Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Methods Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial–mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68+ and CD163+ macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. Results In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68+ macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial–mesenchymal transition. Conclusion In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype.http://link.springer.com/article/10.1186/s13287-017-0669-0Pulmonary arterial hypertensionMesenchymal stromal cellsHemodynamicsLung vascular remodelingMacrophage phenotype |
| spellingShingle | Lucas de Mendonça Nathane S. Felix Natália G. Blanco Jaqueline S. Da Silva Tatiana P. Ferreira Soraia C. Abreu Fernanda F. Cruz Nazareth Rocha Patrícia M. Silva Vanessa Martins Vera L. Capelozzi Gizele Zapata-Sudo Patricia R. M. Rocco Pedro L. Silva Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension Stem Cell Research & Therapy Pulmonary arterial hypertension Mesenchymal stromal cells Hemodynamics Lung vascular remodeling Macrophage phenotype |
| title | Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| title_full | Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| title_fullStr | Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| title_full_unstemmed | Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| title_short | Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| title_sort | mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension |
| topic | Pulmonary arterial hypertension Mesenchymal stromal cells Hemodynamics Lung vascular remodeling Macrophage phenotype |
| url | http://link.springer.com/article/10.1186/s13287-017-0669-0 |
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