Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival.
Prospectively defined murine mesenchymal stem cells inhibit Klebsiella pneumoniae-induced acute lung injury and improve pneumonia survival.
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DOI：
10.1186/s12931-015-0288-1
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发表时间：
2015-10-06
影响因子：
5.8
通讯作者：
Baal N
中科院分区：
文献类型：
--
作者：
Hackstein H;Lippitsch A;Krug P;Schevtschenko I;Kranz S;Hecker M;Dietert K;Gruber AD;Bein G;Brendel C;Baal N
许多研究已经描述了间充质干细胞（MSC）的免疫抑制能力，但是这些研究使用异质祖细胞的混合物进行体外扩增。最近，基于PDFGR α + SCA 1 + CD 45 − TER 119 −（PαS）表达，在小鼠骨髓（BM）中前瞻性地鉴定了多能MSC，但这些MSC的免疫调节能力尚不清楚。我们通过小鼠骨髓的高纯度FACS分选分离出PαS MSC，并在体外扩增后，我们分析了急性肺炎期间的体内免疫调节活性。在肺炎克雷伯菌急性呼吸道感染后4 h，将PαS MSC（1 × 10 6）植入气管内。PαS MSC处理导致肺泡炎和蛋白渗漏与模拟处理对照相比显著减少。经PαS MSC处理的小鼠肺泡TNF-α和IL-12 p70表达显著降低，而IL-10表达不受影响。多参数流式细胞术分析呼吸道树突状细胞（DC）亚群显示，PαS MSC处理的小鼠肺DC浸润显著减少，肺CD 103 + DC上CD 86共刺激分子表达显著减少。在肺炎后急性期，PαS MSC处理的动物表现出呼吸道IL-17+ CD 4 + T细胞和IFN-γ+ CD 4 + T细胞显著减少。此外，PαS MSC治疗显著改善了总体肺炎存活率，并且没有增加细菌负荷。在这项研究中，我们首次证明了前瞻性定义的MSC在肺炎中的可行性和体内免疫调节能力。本文的在线版本（doi：10.1186/s12931-015-0288-1）包含补充材料，可供授权用户使用。
Numerous studies have described the immunosuppressive capacity of mesenchymal stem cells (MSC) but these studies use mixtures of heterogeneous progenitor cells for in vitro expansion. Recently, multipotent MSC have been prospectively identified in murine bone marrow (BM) on the basis of PDFGRa+ SCA1+ CD45− TER119− (PαS) expression but the immunomodulatory capacity of these MSC is unknown. We isolated PαS MSC by high-purity FACS sorting of murine BM and after in vitro expansion we analyzed the in vivo immunomodulatory activity during acute pneumonia. PαS MSC (1 × 106) were applied intratracheally 4 h after acute respiratory Klebsiella pneumoniae induced infection. PαS MSC treatment resulted in significantly reduced alveolitis and protein leakage in comparison to mock-treated controls. PαS MSC-treated mice exhibited significantly reduced alveolar TNF-α and IL-12p70 expression, while IL-10 expression was unaffected. Dissection of respiratory dendritic cell (DC) subsets by multiparameter flow cytometry revealed significantly reduced lung DC infiltration and significantly reduced CD86 costimulatory expression on lung CD103+ DC in PαS MSC-treated mice. In the post-acute phase of pneumonia, PαS MSC-treated animals exhibited significantly reduced respiratory IL-17+ CD4+ T cells and IFN-γ+ CD4+ T cells. Moreover, PαS MSC treatment significantly improved overall pneumonia survival and did not increase bacterial load. In this study we demonstrated for the first time the feasibility and in vivo immunomodulatory capacity of prospectively defined MSC in pneumonia. The online version of this article (doi:10.1186/s12931-015-0288-1) contains supplementary material, which is available to authorized users.