Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS.
Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS.
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DOI：
10.1002/stem.2372
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Krasnodembskaya AD
中科院分区：
文献类型：
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作者：
Jackson MV;Morrison TJ;Doherty DF;McAuley DF;Matthay MA;Kissenpfennig A;O'Kane CM;Krasnodembskaya AD
间充质基质细胞（MSC）已被报道在急性呼吸窘迫综合征（ARDS）和脓毒症的临床前模型中改善细菌清除。这种效应的机制尚未完全阐明。本研究的主要目的是研究MSC在体内的抗微生物作用取决于其对通过线粒体转移发生的巨噬细胞吞噬活性的调节的假设。我们建立了选择性消耗肺泡巨噬细胞（AM）与鼻内（IN）给药脂质体氯膦酸盐导致在大肠杆菌肺炎的体内模型中MSC的抗菌作用完全废除。此外，我们发现，MSC管理与增强AM吞噬在体内。我们发现MSC与单核细胞衍生的巨噬细胞直接共培养增强了它们的吞噬能力。通过荧光成像和流式细胞术，我们证明了从MSC到巨噬细胞的广泛线粒体转移，至少部分通过隧道纳米管（TNT）样结构发生。我们还检测到肺巨噬细胞在体内很容易获得MSC线粒体，并且MSC线粒体阳性的巨噬细胞表现出更明显的吞噬活性。最后，通过MSC阻断TNT形成而部分抑制线粒体转移导致未能改善巨噬细胞生物能量学，并且完全消除了MSC对体外巨噬细胞吞噬作用的影响和MSC在体内的抗微生物作用。总的来说，这项工作首次证明了从MSC到先天免疫细胞的线粒体转移导致吞噬活性的增强，并揭示了MSC在ARDS中的抗微生物作用的重要新机制。干细胞2016;34：2210-2223
Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte‐derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)‐like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210–2223