Zhu Ying-Gang, Feng Xiao-Mei, Abbott Jason, Fang Xiao-Hui, Hao Qi, Monsel Antoine, Qu Jie-Ming, Matthay Michael A, Lee Jae W
Department of Pulmonary Medicine, Huadong Hospital, Fudan University, Shanghai, People's Republic of China.
Stem Cells. 2014 Jan;32(1):116-25. doi: 10.1002/stem.1504.
We previously found that human mesenchymal stem cells (MSC) or its conditioned medium restored lung protein permeability and reduced alveolar inflammation following Escherichia coli endotoxin-induced acute lung injury (ALI) in an ex vivo perfused human lung in part through the secretion of soluble factors such as keratinocyte growth factor (KGF). Recently, MSC were found to release microvesicles (MVs) that were biologically active because of the presence of mRNA or miRNA with reparative properties. MVs are circular fragments of membrane released from the endosomal compartment as exosomes or shed from the surface membranes. These studies were designed to determine if MVs released by human bone marrow derived MSCs would be effective in restoring lung protein permeability and reducing inflammation in E. coli endotoxin-induced ALI in C57BL/6 mice. The intratracheal instillation of MVs improved several indices of ALI at 48 hours. Compared to endotoxin-injured mice, MVs reduced extravascular lung water by 43% and reduced total protein levels in the bronchoalveolar lavage (BAL) fluid by 35%, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid by 73% and 49%, respectively, demonstrating a reduction in inflammation. KGF siRNA-pretreatment of MSC partially eliminated the therapeutic effects of MVs released by MSCs, suggesting that KGF protein expression was important for the underlying mechanism. In summary, human MSC-derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus.
我们之前发现，人骨髓间充质干细胞（MSC）或其条件培养基可恢复肺蛋白通透性，并减轻大肠杆菌内毒素诱导的急性肺损伤（ALI）后离体灌注人肺中的肺泡炎症，部分原因是通过分泌角质形成细胞生长因子（KGF）等可溶性因子。最近，发现MSC会释放具有生物活性的微泡（MV），因为其中存在具有修复特性的mRNA或miRNA。MV是从内体区室释放出来的圆形膜片段，即外泌体，或从表面膜脱落。这些研究旨在确定人骨髓来源的MSC释放的MV是否能有效恢复C57BL/6小鼠中大肠杆菌内毒素诱导的ALI的肺蛋白通透性并减轻炎症。气管内滴注MV可在48小时时改善ALI的几个指标。与内毒素损伤的小鼠相比，MV使血管外肺水减少43%，并使支气管肺泡灌洗（BAL）液中的总蛋白水平降低35%，表明肺水肿和肺蛋白通透性降低。MV还分别使BAL液中的中性粒细胞流入和巨噬细胞炎性蛋白-2水平降低73%和49%，表明炎症减轻。对MSC进行KGF siRNA预处理可部分消除MSC释放的MV的治疗效果，这表明KGF蛋白表达对潜在机制很重要。总之，人MSC来源的MV在小鼠大肠杆菌内毒素诱导的ALI后具有治疗效果，部分原因是受损肺泡中KGF mRNA的表达。
