Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia; Division of Immunology, Immunity to Infection and Respiratory Medicine, The University of Manchester, Manchester, England, UK.
Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI) and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Biomed Pharmacother. 2024 Sep;178:117259. doi: 10.1016/j.biopha.2024.117259. Epub 2024 Aug 7.
Idiopathic pulmonary fibrosis (IPF) is characterised by lung scarring and stiffening, for which there is no effective cure. Based on the immunomodulatory and anti-fibrotic effects of induced pluripotent stem cell (iPSC) and mesenchymoangioblast-derived mesenchymal stem cells (iPSCs-MSCs), this study evaluated the therapeutic effects of iPSCs-MSCs in a bleomycin (BLM)-induced model of pulmonary fibrosis. Adult male C57BL/6 mice received a double administration of BLM (0.15 mg/day) 7-days apart and were then maintained for a further 28-days (until day-35), whilst control mice were administered saline 7-days apart and maintained for the same time-period. Sub-groups of BLM-injured mice were intravenously-injected with 1×10 iPSC-MSCs on day-21 alone or on day-21 and day-28 and left until day-35 post-injury. Measures of lung inflammation, fibrosis and compliance were then evaluated. BLM-injured mice presented with lung inflammation characterised by increased immune cell infiltration and increased pro-inflammatory cytokine expression, epithelial damage, lung transforming growth factor (TGF)-β1 activity, myofibroblast differentiation, interstitial collagen fibre deposition and topology (fibrosis), in conjunction with reduced matrix metalloproteinase (MMP)-to-tissue inhibitor of metalloproteinase (TIMP) ratios and dynamic lung compliance. All these measures were ameliorated by a single or once-weekly intravenous-administration of iPSC-MSCs, with the latter reducing dendritic cell infiltration and lung epithelial damage, whilst promoting anti-inflammatory interleukin (IL)-10 levels to a greater extent. Proteomic profiling of the conditioned media of cultured iPSC-MSCs that were stimulated with TNF-α and IFN-γ, revealed that these stem cells secreted protein levels of immunosuppressive factors that contributed to the anti-fibrotic and therapeutic potential of iPSCs-MSCs as a novel treatment option for IPF.
特发性肺纤维化（IPF）的特征是肺部瘢痕和僵硬，目前尚无有效的治疗方法。基于诱导多能干细胞（iPSC）和间充质血管前体细胞衍生的间充质干细胞（iPSCs-MSCs）的免疫调节和抗纤维化作用，本研究评估了 iPSCs-MSCs 在博来霉素（BLM）诱导的肺纤维化模型中的治疗效果。成年雄性 C57BL/6 小鼠接受 BLM（0.15mg/天）两次给药，间隔 7 天，然后再维持 28 天（直至第 35 天），而对照组小鼠接受盐水两次给药，间隔 7 天，并维持相同的时间。BLM 损伤小鼠亚组在第 21 天单独或第 21 天和第 28 天接受 1×10iPSC-MSCs 静脉注射，并在受伤后第 35 天进行评估。然后评估肺炎症、纤维化和顺应性的措施。BLM 损伤的小鼠表现出以免疫细胞浸润增加和促炎细胞因子表达增加、上皮损伤、肺转化生长因子（TGF）-β1 活性、肌成纤维细胞分化、间质胶原纤维沉积和拓扑结构（纤维化）为特征的肺炎症，同时伴有基质金属蛋白酶（MMP）-组织金属蛋白酶抑制剂（TIMP）比值和动态肺顺应性降低。单次或每周一次静脉注射 iPSC-MSCs 可改善所有这些指标，后者可减少树突状细胞浸润和肺上皮损伤，同时更有效地促进抗炎白细胞介素（IL）-10 水平。用 TNF-α和 IFN-γ刺激培养的 iPSC-MSCs 的条件培养基的蛋白质组学分析表明，这些干细胞分泌的免疫抑制因子的蛋白水平有助于 iPSCs-MSCs 的抗纤维化和治疗潜力，作为 IPF 的一种新的治疗选择。
