The Anti-asthmatic Effect of Intratracheally Treated Mesenchymal Stem Cells via Modulation of Lung Macrophage Activation

BackgroundMesenchymal stem cells (MSCs) possess immunomodulatory properties that provide therapeutic potential for the treatment of inflammatory diseases. While the therapeutic and clinical effects of MSCs are partially known, the effects of its administration to the airway in asthma, a chronic airway inflammatory disease, remain unclear.MethodsSix-week-old female BALB/c mice were sensitized and challenged with ovalbumin. The effects of intratracheally administered umbilical cord MSCs were evaluated by measuring airway hyperresponsiveness, airway inflammatory cell analysis, histological analysis, flow cytometry, and quantitative real-time PCR. Furthermore, ex vivo experiments confirmed the effect of MSC treatment on macrophages that originated from bronchoalveolar lavage fluid and were treated with interleukin (IL)-4 to induce M2 activation. Additionally, an in vitro transwell assay confirmed the effect of MSCs on macrophage activation through direct or indirect treatment using the CRL-2019 alveolar macrophage (AM) cell line.ResultsIntratracheal administration of MSCs significantly decreased the elevated levels of inflammatory cells and airway resistance in the murine asthma model. MSC administration also significantly decreased the numbers of Th2 cells, ILC2, and macrophages in the lungs of asthmatic mice. In particular, MHCII and CD86 expression was prominently reduced in dendritic cells and AMs following MSC treatment. Suppressed SiglecF+CD11c+CD11b- resident AMs, presenting strong negative correlation with type II inflammatory cells such as Th2 cells, ILC2, and eosinophils, were restored by intratracheal MSC treatment. Typical macrophage polarization to M2, particularly M2a, was significantly diminished. Expression levels of markers presenting M2 polarization and Th2 inflammation were decreased in the asthma model upon MSC administration. Ex vivo experiments of IL-4 treated AMs confirmed that MSC treatment reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla. In vitro experiments of IL-4 treated AMs confirmed that both direct and indirect MSC treatments through transwells significantly reduced Il-5 and Il-13 expression. No difference between the two treatment methods was found.ConclusionsUmbilical cord MSCs appear to regulate pulmonary macrophages, suppress Th2 inflammation, and mediate anti-asthmatic effects via soluble mediators.