Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20, Prague 4, Czech Republic.
Department of Cell Biology, Faculty of Science, Charles University, 128 43, Prague 2, Czech Republic.
Stem Cell Rev Rep. 2019 Dec;15(6):880-891. doi: 10.1007/s12015-019-09908-0.
Retinal degenerative disorders are characterized by a local upregulation of inflammatory factors, infiltration with cells of the immune system, a vascular dysfunction and by the damage of retinal cells. There is still a lack of treatment protocols for these diseases. Mesenchymal stem cell (MSC)-based therapy using immunoregulatory, regenerative and differentiating properties of MSCs offers a promising treatment option. In this study, we analyzed the immunomodulatory properties of mouse bone marrow-derived MSCs after their intravitreal delivery to the inflammatory environment in the eye, caused by the application of pro-inflammatory cytokines IL-1β, TNF-α and IFN-γ. The intravitreal administration of these cytokines induces an increased expression of pro-inflammatory molecules such as IL-1α, IL-6, inducible nitric oxide synthase, TNF-α and vascular endothelial growth factor in the retina. However, a significant decrease in the expression of genes for all these pro-inflammatory molecules was observed after the intravitreal injection of MSCs. We further showed that an increased infiltration of the retina with immune cells, mainly with macrophages, which was observed after pro-inflammatory cytokine application, was significantly reduced after the intravitreal application of MSCs. The similar immunosuppressive effects of MSCs were also demonstrated in vitro in cultures of cytokine-stimulated retinal explants and MSCs. Overall, the results show that intravitreal application of MSCs inhibits the early retinal inflammation caused by pro-inflammatory cytokines, and propose MSCs as a promising candidate for stem cell-based therapy of retinal degenerative diseases.
视网膜退行性疾病的特征是局部炎症因子上调、免疫系统细胞浸润、血管功能障碍和视网膜细胞损伤。目前，这些疾病仍然缺乏治疗方案。基于间充质干细胞（MSC）的治疗方法利用 MSC 的免疫调节、再生和分化特性，提供了一种有前途的治疗选择。在这项研究中，我们分析了在眼部炎症环境中，即通过应用促炎细胞因子 IL-1β、TNF-α 和 IFN-γ 引起的炎症环境中，小鼠骨髓来源的 MSC 的免疫调节特性。这些细胞因子的玻璃体内给药会导致视网膜中促炎分子（如 IL-1α、IL-6、诱导型一氧化氮合酶、TNF-α 和血管内皮生长因子）的表达增加。然而，在玻璃体内注射 MSC 后，所有这些促炎分子的基因表达都显著下降。我们进一步表明，在应用促炎细胞因子后观察到的视网膜内免疫细胞（主要是巨噬细胞）浸润增加，在玻璃体内应用 MSC 后显著减少。在细胞因子刺激的视网膜外植体和 MSC 的体外培养中也观察到了 MSC 的类似免疫抑制作用。总体而言，这些结果表明，玻璃体内注射 MSC 可抑制促炎细胞因子引起的早期视网膜炎症，并提出 MSC 作为治疗视网膜退行性疾病的基于干细胞治疗的有前途的候选物。
