Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis
Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulat...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6467 |
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| author | Sandra Tejedor Marc Buigues Hernán González-King Andreia M. Silva Nahuel Aquiles García Niek Dekker Pilar Sepúlveda |
| author_facet | Sandra Tejedor Marc Buigues Hernán González-King Andreia M. Silva Nahuel Aquiles García Niek Dekker Pilar Sepúlveda |
| author_sort | Sandra Tejedor |
| collection | DOAJ |
| description | Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-β1) expression and extracellular matrix deposition. Small extracellular vesicles (SEVs) from mesenchymal stromal cells (MSCs) are being investigated to treat myocardial infarction, using different strategies to bolster their therapeutic ability. Here, we generated TERT-immortalized human MSC cell lines (MSC-T) engineered to overexpress two forms of cleavage-resistant OSM fused to CD81TM (OSM-SEVs), which allows the display of the cytokine at the surface of secreted SEVs. The therapeutic potential of OSM-SEVs was assessed in vitro using human cardiac ventricular fibroblasts (HCF-Vs) activated by TGF-β1. Compared with control SEVs, OSM-loaded SEVs reduced proliferation in HCF-V and blunted telo-collagen expression. When injected intraperitoneally into mice treated with isoproterenol, OSM-loaded SEVs reduced fibrosis, prevented cardiac hypertrophy, and increased angiogenesis. Overall, we demonstrate that the enrichment of functional OSM on the surface of MSC-T-SEVs increases their potency in terms of anti-fibrotic and pro-angiogenic properties, which opens new perspectives for this novel biological product in cell-free-based therapies. |
| first_indexed | 2024-03-11T05:34:46Z |
| format | Article |
| id | doaj.art-50c689bfd584474f820e1b0637e331aa |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:34:46Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-50c689bfd584474f820e1b0637e331aa2023-11-17T16:51:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01247646710.3390/ijms24076467Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance AngiogenesisSandra Tejedor0Marc Buigues1Hernán González-King2Andreia M. Silva3Nahuel Aquiles García4Niek Dekker5Pilar Sepúlveda6Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainRegenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainRegenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainDiscovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 43183 Gothenburg, SwedenRegenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainDiscovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 43183 Gothenburg, SwedenRegenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, SpainMyocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-β1) expression and extracellular matrix deposition. Small extracellular vesicles (SEVs) from mesenchymal stromal cells (MSCs) are being investigated to treat myocardial infarction, using different strategies to bolster their therapeutic ability. Here, we generated TERT-immortalized human MSC cell lines (MSC-T) engineered to overexpress two forms of cleavage-resistant OSM fused to CD81TM (OSM-SEVs), which allows the display of the cytokine at the surface of secreted SEVs. The therapeutic potential of OSM-SEVs was assessed in vitro using human cardiac ventricular fibroblasts (HCF-Vs) activated by TGF-β1. Compared with control SEVs, OSM-loaded SEVs reduced proliferation in HCF-V and blunted telo-collagen expression. When injected intraperitoneally into mice treated with isoproterenol, OSM-loaded SEVs reduced fibrosis, prevented cardiac hypertrophy, and increased angiogenesis. Overall, we demonstrate that the enrichment of functional OSM on the surface of MSC-T-SEVs increases their potency in terms of anti-fibrotic and pro-angiogenic properties, which opens new perspectives for this novel biological product in cell-free-based therapies.https://www.mdpi.com/1422-0067/24/7/6467extracellular vesiclesOncostatin Mfibrosisisoproterenolmesenchymal stem cells |
| spellingShingle | Sandra Tejedor Marc Buigues Hernán González-King Andreia M. Silva Nahuel Aquiles García Niek Dekker Pilar Sepúlveda Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis International Journal of Molecular Sciences extracellular vesicles Oncostatin M fibrosis isoproterenol mesenchymal stem cells |
| title | Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis |
| title_full | Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis |
| title_fullStr | Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis |
| title_full_unstemmed | Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis |
| title_short | Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis |
| title_sort | oncostatin m enriched small extracellular vesicles derived from mesenchymal stem cells prevent isoproterenol induced fibrosis and enhance angiogenesis |
| topic | extracellular vesicles Oncostatin M fibrosis isoproterenol mesenchymal stem cells |
| url | https://www.mdpi.com/1422-0067/24/7/6467 |
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