Background

Oxidative stress–induced mitochondrial dysfunction can contribute to inflammation and remodeling in patients with chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells.

Objective

We sought to examine the effect of induced pluripotent stem cell–derived mesenchymal stem cells (iPSC-MSCs) on oxidative stress–induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo.

Methods

ASMCs were cocultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), and apoptosis were measured. Conditioned medium from iPSC-MSCs and transwell cocultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyperresponsiveness in ozone-exposed mice was also investigated.

Results

Coculture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis, and ΔΨm loss in ASMCs. iPSC-MSC–conditioned medium or transwell cocultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct coculture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyperresponsiveness, and inflammation in mouse lungs.

Conclusion

iPSC-MSCs offered protection against oxidative stress–induced mitochondrial dysfunction in human ASMCs and in mouse lungs while reducing airway inflammation and hyperresponsiveness. These effects are, at least in part, dependent on cell-cell contact, which allows for mitochondrial transfer, and paracrine regulation. Therefore iPSC-MSCs show promise as a therapy for oxidative stress–dependent lung diseases, such as COPD.

中文翻译：

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间充质干细胞缓解氧化应激引起的气道线粒体功能障碍

背景

氧化应激引起的线粒体功能障碍可导致慢性阻塞性肺疾病（COPD）患者的炎症和重塑。在COPD的动物模型中，间充质干细胞可防止肺损伤。尚不清楚这些作用是否通过减轻气道细胞中的线粒体功能障碍而发生。

客观的

我们试图检查诱导的多能干细胞来源的间充质干细胞（iPSC-MSCs）在体外和小鼠肺中对人呼吸道平滑肌细胞（ASMCs）的氧化应激诱导的线粒体功能障碍的作用。

方法

将ASMC与iPSC-MSC在香烟烟雾培养基（CSM）存在下共培养，并测量线粒体活性氧（ROS）水平，线粒体膜电位（ΔΨm）和细胞凋亡。来自iPSC-MSC和transwell共培养的条件培养基用于检测任何旁分泌作用。还研究了全身注射iPSC-MSC对暴露于臭氧的小鼠的气道炎症和高反应性的影响。

结果

iPSC-MSC与ASMC的共培养可减弱CSM诱导的ASMC中的线粒体ROS，细胞凋亡和ΔΨm损失。iPSC-MSC条件培养液或与iPSC-MSC一起的transwell共培养可降低CSM诱导的线粒体ROS，但不能降低ΔΨm或ASMC中的细胞凋亡。直接共培养后观察到了从iPSC-MSC到ASMC的线粒体转移，并被CSM增强。iPSC-MSC可减轻臭氧诱导的线粒体功能障碍，气道高反应性和小鼠肺部炎症。

结论

iPSC-MSC可在人类气管平滑肌细胞和小鼠肺部中抵抗氧化应激引起的线粒体功能障碍，同时减少气道炎症和反应过度。这些作用至少部分取决于细胞间的接触，从而允许线粒体转移和旁分泌调节。因此，iPSC-MSCs有望作为一种治疗氧化应激依赖型肺部疾病（如COPD）的疗法。