Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Nat Med. 2012 Apr 15;18(5):759-65. doi: 10.1038/nm.2736.
Bone marrow-derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in this protection, we airway-instilled mice first with lipopolysaccharide (LPS) and then with either mouse BMSCs (mBMSCs) or human BMSCs (hBMSCs). Live optical studies revealed that the mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelia in these mice, releasing mitochondria-containing microvesicles that the epithelia engulfed. The presence of BMSC-derived mitochondria in the epithelia was evident optically, as well as by the presence of human mitochondrial DNA in mouse lungs instilled with hBMSCs. The mitochondrial transfer resulted in increased alveolar ATP concentrations. LPS-induced ALI, as indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by the instillation of wild-type mBMSCs but not of mutant, GJC-incompetent mBMSCs or mBMSCs with dysfunctional mitochondria. This is the first evidence, to our knowledge, that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.
骨髓基质细胞 (BMSCs) 可保护急性肺损伤 (ALI)。为了确定 BMSC 线粒体在此保护中的作用，我们首先用脂多糖 (LPS) 气道内滴注小鼠，然后再用小鼠 BMSCs (mBMSCs) 或人 BMSCs (hBMSCs)。活光学研究显示，mBMSCs 与这些小鼠的肺泡上皮形成含有连接蛋白 43 (Cx43) 的间隙连接通道 (GJCs)，释放含有线粒体的微囊泡，上皮细胞吞噬这些微囊泡。光学上以及在注入 hBMSCs 的小鼠肺中存在人线粒体 DNA，均表明上皮细胞中存在 BMSC 衍生的线粒体。线粒体转移导致肺泡 ATP 浓度增加。用野生型 mBMSCs 而不是间隙连接无能的突变型 mBMSCs 或线粒体功能障碍的 mBMSCs 进行气道内滴注，可显著减轻 LPS 诱导的 ALI，如肺泡白细胞增多和蛋白渗漏、表面活性剂分泌抑制和高死亡率所表明的那样。这是我们所知的第一个证据，表明 BMSCs 通过 Cx43 依赖性肺泡附着和线粒体转移来恢复肺泡生物能量学，从而保护 ALI。
