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.
Int J Mol Sci. 2023 Mar 30;24(7):6467. doi: 10.3390/ijms24076467.
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.
心肌纤维化是心脏功能障碍的病理标志。肿瘤坏死因子样细胞因子（Oncostatin M，OSM）是一种多功能细胞因子，在持续暴露于不同器官后可促进纤维化。然而，心肌纤维化过程中巨噬细胞释放的 OSM 通过调节转化生长因子-β1（transforming growth factor beta 1，TGF-β1）表达和细胞外基质沉积来抑制心肌成纤维细胞的激活。人们正在研究间充质基质细胞（mesenchymal stromal cells，MSCs）来源的小细胞外囊泡（small extracellular vesicles，SEVs），以不同策略来增强其治疗能力，用于治疗心肌梗死。在此，我们生成了永生化的人 MSC 细胞系（MSC-T），通过基因工程过表达两种形式的与 CD81TM 融合的不易被切割的 OSM（OSM-SEVs），使细胞因子能够在分泌的 SEVs 表面表达。通过 TGF-β1 激活的人心肌成纤维细胞（human cardiac ventricular fibroblasts，HCF-V），在体外评估了 OSM-SEVs 的治疗潜力。与对照 SEVs 相比，负载 OSM 的 SEVs 减少了 HCF-V 的增殖，并减弱了端胶原的表达。当将负载 OSM 的 SEVs 腹膜内注射到异丙肾上腺素处理的小鼠中时，其减少了纤维化、预防了心脏肥大并增加了血管生成。总之，我们证明了 MSC-T-SEVs 表面功能化的 OSM 丰度增加了其抗纤维化和促血管生成特性的效力，为这种新型无细胞治疗生物产品开辟了新的前景。
