Hackstein Holger, Lippitsch Anne, Krug Philipp, Schevtschenko Inna, Kranz Sabine, Hecker Matthias, Dietert Kristina, Gruber Achim D, Bein Gregor, Brendel Cornelia, Baal Nelli
Institute for Clinical Immunology and Transfusion Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Langhansstr. 7, D-35390, Giessen, Germany.
Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), University Hospital Giessen und Marburg, Justus-Liebig-University Giessen, Giessen, Germany.
Respir Res. 2015 Oct 6;16:123. doi: 10.1186/s12931-015-0288-1.
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 × 10(6)) 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.
众多研究描述了间充质干细胞（MSC）的免疫抑制能力，但这些研究使用异质性祖细胞混合物进行体外扩增。最近，基于血小板衍生生长因子受体α（PDFGRα）+干细胞抗原1（SCA1）+ CD45- TER119-（PαS）的表达，在小鼠骨髓（BM）中前瞻性地鉴定出了多能MSC，但这些MSC的免疫调节能力尚不清楚。
我们通过对小鼠骨髓进行高纯度荧光激活细胞分选（FACS）来分离PαS MSC，体外扩增后，分析其在急性肺炎期间的体内免疫调节活性。在急性呼吸道肺炎克雷伯菌诱导感染后4小时，经气管内给予PαS MSC（1×10⁶）。
与模拟处理的对照组相比，PαS MSC治疗导致肺泡炎和蛋白质渗漏显著减少。接受PαS MSC治疗的小鼠肺泡肿瘤坏死因子-α（TNF-α）和白细胞介素-12p70表达显著降低，而白细胞介素-10表达未受影响。通过多参数流式细胞术分析呼吸道树突状细胞（DC）亚群发现，接受PαS MSC治疗的小鼠肺DC浸润显著减少，肺CD103⁺ DC上的共刺激分子CD86表达显著降低。在肺炎的急性期后，接受PαS MSC治疗的动物呼吸道白细胞介素-17⁺ CD4⁺ T细胞和干扰素-γ⁺ CD4⁺ T细胞显著减少。此外，PαS MSC治疗显著提高了肺炎的总体生存率，且未增加细菌载量。
在本研究中，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。
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