Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes
Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes
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DOI：
10.1172/jci.insight.128060
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发表时间：
2019-11-01
期刊：
影响因子：
8
通讯作者：
Kourembanas, Stella
中科院分区：
文献类型：
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作者：
Mansouri, Nahal;Willis, Gareth R.;Kourembanas, Stella
间充质基质/干细胞（MSC）疗法在特发性肺纤维化（IPF）的实验模型中显示出前景。本研究的目的是测试由人BM MSC（MEx）产生的细胞外囊泡在博来霉素诱导的肺纤维化模型中的治疗效果并研究作用机制。成年C57 BL/6小鼠用气管内滴注博来霉素进行攻击，并在第7天或第21天同时用MEx处理，或用于逆转模型。在第7、14或28天评估实验组。博来霉素激发的小鼠表现出严重的间隔增厚和显著的纤维化，并且这通过MEx治疗有效地预防或逆转。MEx调节肺巨噬细胞表型，将肺促炎/经典和非经典单核细胞和肺泡巨噬细胞的比例向对照小鼠的单核细胞/巨噬细胞分布转移。在BM中证明了平行的免疫调节作用。值得注意的是，Mex预处理的BM衍生的单核细胞的移植减轻了肺纤维化和肺部炎症的核心特征。蛋白质组学分析显示，MEx疗法促进免疫调节、抗炎单核细胞表型。我们的结论是，MEx预防和逆转博莱霉素诱导的肺纤维化的核心特征，MEx的有益作用可能是通过系统调节单核细胞表型介导的。
Mesenchymal stromal/stem cell (MSC) therapy has shown promise in experimental models of idiopathic pulmonary fibrosis (IPF). The aim of this study was to test the therapeutic effects of extracellular vesicles produced by human BM MSCs (MEx) in a bleomycin- induced pulmonary fibrosis model and investigate mechanisms of action. Adult C57BL/6 mice were challenged with endotracheal instillation of bleomycin and treated with MEx concurrently, or for reversal models, at day 7 or 21. Experimental groups were assessed at day 7, 14, or 28. Bleomycin-challenged mice presented with severe septal thickening and prominent fibrosis, and this was effectively prevented or reversed by MEx treatment. MEx modulated lung macrophage phenotypes, shifting the proportions of lung proinflammatory/classical and nonclassical monocytes and alveolar macrophages toward the monocyte/macrophage profiles of control mice. A parallel immunomodulatory effect was demonstrated in the BM. Notably, transplantation of MEx-preconditioned BM-derived monocytes alleviated core features of pulmonary fibrosis and lung inflammation. Proteomic analysis revealed that MEx therapy promotes an immunoregulatory, anti-inflammatory monocyte phenotype. We conclude that MEx prevent and revert core features of bleomycin-induced pulmonary fibrosis and that the beneficial actions of MEx may be mediated via systemic modulation of monocyte phenotypes.