Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis.

Fecha de publicación: 30/03/2023 Fecha Ahead of Print: 30/03/2023

Autores de IIS La Fe

Sandra Tejedor Gascón

Autor
Marc Buigues Caravaca

Autor
Hernán González King Garibotti

Autor
Nahuel Aquiles Garcia

Autor
Pilar Sepúlveda Sanchis

Autor

Participantes ajenos a IIS La Fe

Silva, Andreia M.
Dekker, Niek

Grupos

Regeneración y Trasplante Cardíaco

Leader

Pilar Sepúlveda Sanchis

Abstract

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-ß1) 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-ß1. 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.

Datos de la publicación

ISSN/ISSNe:: 1661-6596, 1661-6596
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms24076467
Factor de Impacto:: 1,176 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

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Métricas

Filiaciones

Tejedor, Sandra:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain

Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 43183 Gothenburg, Sweden
Buigues, Marc:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
Gonzalez-King, Hernan:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain

Early Cardiovascular Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, 43183 Gothenburg, Sweden
Silva, Andreia M.:: Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 43183 Gothenburg, Sweden
Garcia, Nahuel Aquiles:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain

GECORP, Av. Juan Manuel de Rosas, Buenos Aires 7220, Argentina
Dekker, Niek:: Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 43183 Gothenburg, Sweden
Sepulveda, Pilar:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain

Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Carlos III Institute of Health, 28029 Madrid, Spain