Lee Jooyeon, Jang Jimin, Cha Sang-Ryul, Lee Se Bi, Hong Seok-Ho, Bae Han-Sol, Lee Young Jin, Yang Se-Ran
Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea.
Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Korea.
Immune Netw. 2023 Dec 18;23(6):e48. doi: 10.4110/in.2023.23.e48. eCollection 2023 Dec.
Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC were associated with migration and growth. MSC ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC. MSC treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3CD25 Treg of CD4 cells were further increased in ALI mice treated with MSC. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.
间充质基质/干细胞（MSCs）具有免疫调节特性，其调节功能代表了急性肺损伤（ALI）的一种潜在治疗方法。然而，在确定MSCs衍生的免疫调节途径方面仍存在不确定性。因此，本研究旨在探讨人重组骨形态发生蛋白-2（rhBMP-2）预处理的胚胎干细胞来源的间充质干细胞（ES-MSCs，简称MSC）在促进ALI小鼠中调节性T细胞（Tregs）方面增强作用的潜在机制。将MSC用100 ng/ml rhBMP-2预处理24小时，然后在气管内注射1 mg/kg脂多糖（LPS）后通过静脉注射给予小鼠。用rhBMP-2处理MSC可显著增加细胞增殖和迁移，细胞因子阵列显示MSC释放的细胞因子与迁移和生长相关。MSC改善了LPS诱导的肺损伤，并降低了暴露于LPS的小鼠中的髓过氧化物酶活性和通透性。在用MSC治疗的ALI小鼠中，通过抑制磷酸化信号转导和转录激活因子1（STAT1），诱导型一氧化氮合酶水平降低，而总谷胱甘肽水平和超氧化物歧化酶活性进一步增加。MSC治疗增加了吲哚胺2,3-双加氧酶（IDO1）的蛋白水平，表明调节性T细胞增加，在用MSC治疗的ALI小鼠中，CD4细胞的叉头框蛋白3（Foxp3）+CD25+调节性T细胞进一步增加。在与MSC和RAW264.7细胞的共培养试验中，MSC中IDO1的蛋白水平进一步诱导。此外，白细胞介素-10（IL-10）的细胞因子释放增强，而白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）均进一步受到抑制。总之，这些发现表明MSC具有通过促进调节性T细胞来减轻呼吸系统疾病大规模炎症的治疗潜力。
