Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS.
Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS.
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DOI：
10.1183/13993003.02978-2020
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Krasnodembskaya AD
中科院分区：
文献类型：
--
作者：
Dutra Silva J;Su Y;Calfee CS;Delucchi KL;Weiss D;McAuley DF;O'Kane C;Krasnodembskaya AD
肺泡上皮-毛细血管屏障破坏是急性呼吸窘迫综合征（ARDS）的一个标志。线粒体功能障碍在ARDS肺泡-毛细血管屏障受损中的作用尚不清楚。间充质基质细胞衍生的细胞外囊泡（MSC-EV）被认为是ARDS的无细胞治疗。线粒体转移被证明对于MSC和MSC-EV的治疗效果是重要的。在此，我们研究了线粒体功能障碍对ARDS中肺泡上皮和内皮屏障损伤的作用，以及MSC-EV通过线粒体转移调节肺泡-毛细血管屏障完整性的能力。原代人小气道上皮和肺微血管内皮细胞和人精密切割肺切片（PCLSs）用内毒素或来自ARDS患者的血浆样品刺激，并用MSC-EV处理，评价屏障特性和线粒体功能。用MSC-EV治疗脂多糖（LPS）损伤的小鼠，并评估肺损伤程度和肺组织的线粒体呼吸。炎症刺激导致两种类型的原代细胞和PCLS中的渗透性增加以及明显的线粒体功能障碍。来源于正常MSC的细胞外囊泡恢复了屏障完整性和正常水平的氧化磷酸化，而不含线粒体的细胞外囊泡制剂是无效的。在体内，线粒体的存在对于细胞外囊泡减少肺损伤和恢复肺组织中线粒体呼吸的能力至关重要。在ARDS环境中，MSC-EV通过至少部分地经由线粒体转移恢复线粒体功能来改善肺泡-毛细血管屏障特性。线粒体功能障碍是ARDS发病的重要机制。线粒体转移对于MSC细胞外囊泡恢复肺泡-毛细血管屏障完整性的能力至关重要。https://bit.ly/2JuqoCY
Alveolar epithelial–capillary barrier disruption is a hallmark of acute respiratory distress syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) are considered as a cell-free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC-EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC-EVs to modulate alveolar–capillary barrier integrity through mitochondrial transfer. Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC-EVs, barrier properties and mitochondrial functions were evaluated. Lipopolysaccharide (LPS)-injured mice were treated with MSC-EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed. Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. Extracellular vesicles derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while an extracellular vesicles preparation which did not contain mitochondria was not effective. In vivo, presence of mitochondria was critical for extracellular vesicles ability to reduce lung injury and restore mitochondrial respiration in the lung tissue. In the ARDS environment, MSC-EVs improve alveolar–capillary barrier properties through restoration of mitochondrial functions at least partially via mitochondrial transfer. This study demonstrates that mitochondrial dysfunction is an important mechanism of ARDS pathogenesis. Mitochondrial transfer is crucial for the ability of MSC extracellular vesicles to restore integrity of the alveolar–capillary barrier. https://bit.ly/2JuqoCY
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影响因子：
2.9
作者：
Lee JH;Park J;Lee JW
通讯作者：
Lee JW
影响因子：
76.2
作者：
Calfee, Carolyn S.;Delucchi, Kevin;Parsons, Polly E.;Thompson, B. Taylor;Ware, Lorraine B.;Matthay, Michael A.
通讯作者：
Matthay, Michael A.
DOI：
10.1164/rccm.201603-0645oc
发表时间：
2017-02-01
影响因子：
24.7
作者：
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通讯作者：
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影响因子：
4.1
作者：
Biswas, S.;Hwang, J. W.;Rahman, I.
通讯作者：
Rahman, I.
DOI：
10.1164/rccm.201208-1460oc
发表时间：
2013-04-01
影响因子：
24.7
作者：
Agrawal, Ashish;Matthay, Michael A.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.