Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer
Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer
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DOI：
10.1164/rccm.201701-0170oc
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发表时间：
2017-11-15
影响因子：
24.7
通讯作者：
Krasnodembskaya, Anna D.
中科院分区：
文献类型：
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作者：
Morrison, Thomas J.;Jackson, Megan V.;Krasnodembskaya, Anna D.
依据：急性呼吸窘迫综合征（ARDS）仍然是危重患者呼吸衰竭的主要原因。间充质基质细胞（MSC）是一种有前途的候选细胞为基础的治疗。然而，MSC在ARDS中的作用机制尚不清楚。在本研究中，我们着重于MSC对巨噬细胞极化的旁分泌作用和细胞外囊泡（EV）介导的线粒体转移的作用。目的：确定人MSC在ARDS环境中对巨噬细胞功能的影响，并阐明这些作用的机制。人单核细胞源性巨噬细胞（MDM）与人MSC非接触共培养，用LPS或支气管肺泡灌洗液（BALF）刺激来自ARDS患者。小鼠肺泡巨噬细胞（AM）培养离体/无人MSC衍生的EV过继转移到LPS-injured mice. Measures和主要结果：MSC抑制细胞因子的产生，增加M2巨噬细胞标志物的表达，并增强吞噬能力的人MDM刺激LPS或ARDS BALF。这些作用部分由表达CD 44的EV介导。用MSC衍生的EV预处理的AM的连续转移减少了LPS损伤小鼠中的炎症和肺损伤。MDM中氧化磷酸化的抑制阻止了MSC的调节作用。使用罗丹明6 G预处理在MSC中产生功能障碍的线粒体也废除了这些effects.Conclusions：在ARDS环境中，MSC通过EV介导的线粒体转移促进了巨噬细胞的吞噬和高度吞噬的表型。MSC诱导的巨噬细胞表型的变化主要依赖于巨噬细胞氧化磷酸化的增强。用MSC衍生的EV治疗的AM在体内改善肺损伤。
Rationale: Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs' effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer.Objectives: To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects.Methods: Human monocyte-derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice.Measurements and Main Results: MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects.Conclusions: In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC-induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo.