Women's Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA.
JCI Insight. 2019 Aug 8;5(17):129359. doi: 10.1172/jci.insight.129359.
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease. A maladaptive epithelium due to chronic injury is a prominent feature and contributor to pathogenic cellular communication in IPF. Recent data highlight the concept of a "reprogrammed" lung epithelium as critical in the development of lung fibrosis. Extracellular vesicles (EVs) are potent mediator of cellular crosstalk, and recent evidence supports their role in lung pathologies such as IPF. Here, we demonstrate that syndecan-1 is overexpressed by the epithelium in the lungs of IPF patients and in murine models after bleomycin injury. Moreover, we find that syndecan-1 is a pro-fibrotic signal that alters alveolar type II (ATII) cell phenotypes by augmenting TGFβ and Wnt signaling among other pro-fibrotic pathways. Importantly, we demonstrate that syndecan-1 controls the packaging of several anti-fibrotic microRNAs into EVs that have broad effects over several fibrogenic signaling networks as a mechanism of regulating epithelial plasticity and pulmonary fibrosis. Collectively, our work reveals new insight into how EVs orchestrate cellular signals that promote lung fibrosis and demonstrate the importance of syndecan-1 in coordinating these programs.
特发性肺纤维化（IPF）是一种慢性且致命的肺部疾病。由于慢性损伤导致的适应性上皮是 IPF 中致病细胞通讯的一个突出特征和贡献因素。最近的数据强调了“重编程”的肺上皮在肺纤维化发展中的关键作用。细胞外囊泡（EVs）是细胞串扰的有效介质，最近的证据支持它们在肺纤维化等肺部疾病中的作用。在这里，我们证明在 IPF 患者的肺部和博来霉素损伤后的小鼠模型中，上皮细胞过度表达 syndecan-1。此外，我们发现 syndecan-1 是一种促纤维化信号，通过增强 TGFβ 和 Wnt 信号等其他促纤维化途径来改变肺泡 II 型（ATII）细胞表型。重要的是，我们证明 syndecan-1 控制着几种抗纤维化 microRNAs 包装到 EVs 中，作为调节上皮可塑性和肺纤维化的机制，这些 EVs 对几个纤维生成信号网络具有广泛的影响。总的来说，我们的工作揭示了 EVs 如何协调促进肺纤维化的细胞信号的新见解，并证明了 syndecan-1 在协调这些程序中的重要性。
