IV Delivery of Induced Pluripotent Stem Cells Attenuates Endotoxin-Induced Acute Lung Injury in Mice
IV Delivery of Induced Pluripotent Stem Cells Attenuates Endotoxin-Induced Acute Lung Injury in Mice
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DOI：
10.1378/chest.11-0539
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发表时间：
2011-11-01
期刊：
影响因子：
9.6
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
--
作者：
Yang, Kuang-Yao;Shih, Hsin-Chin;Chiou, Shih-Hwa
背景：诱导多能干细胞（IPS）是一种新型的细胞群，但IPS细胞在急性肺损伤（ALI）中的作用目前尚不清楚。我们研究了iPS细胞在改变内毒素诱导的ALI的病理生理中的作用。方法：选取雄性C57BLJ6 8 ~ 12周龄小鼠。气管内注入内毒素4 h后，通过小鼠尾静脉递送小鼠iPS细胞。结果：体内放射性核素显像和体外hoechst标记荧光染色显示，ALI小鼠的肺组织病理学结果、肺细胞因子水平和功能参数比对照组小鼠更多地整合到肺中。iPS细胞显著降低ALI的组织病理学改变和肺损伤评分。免疫染色、电泳迁移率转移试验证实，在ips细胞治疗的ALI小鼠中，核因子κ B （nf - κ B）活性和肺中性粒细胞积累也显著降低，髓过氧化物酶活性也显著降低。这些保护作用在成纤维细胞对照细胞治疗中没有得到复制。iPS细胞介导对内毒素的促炎反应下调（降低肿瘤坏死因子- α、IL-6和巨噬细胞炎症肽-2）。此外，iPS细胞挽救了ALI的低氧血症和肺功能，用iPS细胞的条件培养基治疗显示出与iPS细胞相似的效果，这可能提示由旁分泌因子介导的iPS的治疗益处。结论：静脉给药iPS细胞对减轻内毒素诱导的ALI的严重程度和改善生理损伤有有益作用，这部分是由NF-kappa B活性和中性粒细胞积累的减少介导的。诱导多能干细胞条件培养基显示出与诱导多能干细胞相同的效果。胸部2011;140 (5): 1243 - 1253
Background: Induced pluripotent stem (IPS) cells are novel stern cell populations, but the role of iPS cells in acute lung injury (ALI) is not currently known. We investigated the effect of iPS cells in modifying the pathophysiology of endotoxin-induced ALI.Methods: Male C57BLJ6 8- to 12-week-old mice were enrolled in this study. Mouse iPS cells were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathologic findings, the pulmonary levels of cytokines, and functional parameters were analyzed after either 24 h or 48 h.Results: More iPS cells integrated into the lungs of mice with ALI than those of the control mice, as demonstrated by in vivo radionuclide imaging and in vitro Hoechst-labeled fluorescent staining. iPS cells significantly diminished the histopathologic changes of ALI and the lung injury score. There was also a significant reduction in the activity of nuclear factor-kappa B (NF-kappa B) and neutrophil accumulation in the lung, confirmed by immunostaining, electrophoretic mobility shift assays, and the decrease of myeloperoxidase activity, in the IPS-cell-treated mice with ALI These protective effects were not replicated by the control cell therapy with fibroblasts. iPS cells mediated a downregulation of the proinflammatory response to endotoxin (reducing tumor necrosis factor-alpha, IL-6, and macrophage inflammatory peptide-2). In addition, iPS cells rescued the hypoxemia and pulmonary function of ALI Treatment with a conditioned medium of iPS cells showed effects similar to those of iPS cells, which may suggest the therapeutic benefits of iPS mediated by paracrine factors.Conclusions: IV delivery of iPS cells provides a beneficial effect to attenuate the severity of endotoxin-induced ALI and improve physiologic impairment, which is partly mediated by a reduction in NF-kappa B activity and neutrophils accumulation. The conditioned medium of iPS cells demonstrated effects equal to those of iPS cells. CHEST 2011; 140(5):1243-1253