CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation.
CD11b+ and Sca-1+ Cells Exert the Main Beneficial Effects of Systemically Administered Bone Marrow-Derived Mononuclear Cells in a Murine Model of Mixed Th2/Th17 Allergic Airway Inflammation.
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DOI：
10.5966/sctm.2015-0141
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发表时间：
2016-04
影响因子：
6
通讯作者：
Weiss DJ
中科院分区：
文献类型：
--
作者：
Cruz FF;Borg ZD;Goodwin M;Coffey AL;Wagner DE;Rocco PR;Weiss DJ
使用严重临床哮喘的小鼠模型来研究哪些骨髓源性单核细胞 (BMDMC) 负责改善气道高反应性和肺部炎症。在此模型中，去除 CD11b 阳性细胞（单核细胞、巨噬细胞、树突状细胞）或 Sca-1 阳性细胞（骨髓来源的间充质基质细胞）的 BMDMC 无法改善这些状况。其他细胞类型的消耗并没有减弱 BMDMC 给药的改善效果。在 Th2 介导的嗜酸性粒细胞过敏性气道炎症小鼠模型中，全身施用骨髓来源的单核细胞 (BMDMC) 或骨髓来源的间充质基质细胞 (MSC) 可减少炎症和气道高反应性 (AHR)。然而，由于 BMDMC 是包含 MSC 的异质群体，因此尚不清楚 MSC 是否单独对 BMDMC 的作用负责。为了确定在 Th2 嗜酸性粒细胞和 Th17 中性粒细胞混合过敏性气道炎症（让人联想到严重临床哮喘）模型中哪些 BMDMC 群体负责改善 AHR 和肺部炎症，从正常 C57Bl/6 小鼠中获得的 BMDMC 连续去除 CD45、CD34、CD11b、CD3、CD19、 CD31 或 Sca-1 阳性细胞。然后评估所得的不同细胞群在同系 C56Bl/6 小鼠中对曲霉菌丝提取物 (AHE) 的粘膜致敏和攻击诱导的混合 Th2/Th17 过敏性气道炎症中减少肺部炎症和 AHR 的能力。在此模型中，去除 CD11b 阳性 (CD11b+) 或 Sca-1 阳性 (Sca-1+) 细胞的 BMDMC 无法改善 AHR 或肺部炎症。其他细胞类型的消耗并没有减弱 BMDMC 给药的改善效果。总之，在当前的过敏性炎症模型中，CD11b+细胞（单核细胞、巨噬细胞、树突状细胞）和Sca-1+细胞（MSC）负责BMDMC的有益作用。这项研究表明，骨髓来源的单核细胞（BMDMC）在改善实验性哮喘方面与骨髓来源的间充质基质细胞（MSC）一样有效。它还表明，不仅 BMDMC 库中存在的 MSC 负责 BMDMC 的有益作用，而且单核细胞也是触发这些作用的最重要的细胞群。所有这些都是在严重过敏性气道炎症的临床相关模型的背景下进行的，因此为严重哮喘患者使用 MSC、BMDMC 以及单核细胞等成体细胞进行细胞治疗的潜在临床应用提供了进一步的支持。
A murine model of severe clinical asthma was used to study which bone marrow-derived mononuclear cells (BMDMCs) are responsible for ameliorating airway hyperresponsiveness and lung inflammation. BMDMCs depleted of either CD11b-positive cells (monocytes, macrophages, dendritic cells) or Sca-1-positive cells (bone marrow-derived mesenchymal stromal cells) were unable to ameliorate these conditions in this model. Depletion of the other cell types did not diminish the ameliorating effects of BMDMC administration. Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) or bone marrow-derived mesenchymal stromal cells (MSCs) reduces inflammation and airway hyperresponsiveness (AHR) in a murine model of Th2-mediated eosinophilic allergic airway inflammation. However, since BMDMCs are a heterogeneous population that includes MSCs, it is unclear whether the MSCs alone are responsible for the BMDMC effects. To determine which BMDMC population(s) is responsible for ameliorating AHR and lung inflammation in a model of mixed Th2-eosinophilic and Th17-neutrophilic allergic airway inflammation, reminiscent of severe clinical asthma, BMDMCs obtained from normal C57Bl/6 mice were serially depleted of CD45, CD34, CD11b, CD3, CD19, CD31, or Sca-1 positive cells. The different resulting cell populations were then assessed for ability to reduce lung inflammation and AHR in mixed Th2/Th17 allergic airway inflammation induced by mucosal sensitization to and challenge with Aspergillus hyphal extract (AHE) in syngeneic C56Bl/6 mice. BMDMCs depleted of either CD11b-positive (CD11b+) or Sca-1-positive (Sca-1+) cells were unable to ameliorate AHR or lung inflammation in this model. Depletion of the other cell types did not diminish the ameliorating effects of BMDMC administration. In conclusion, in the current model of allergic inflammation, CD11b+ cells (monocytes, macrophages, dendritic cells) and Sca-1+ cells (MSCs) are responsible for the beneficial effects of BMDMCs. This study shows that bone marrow-derived mononuclear cells (BMDMCs) are as effective as bone marrow-derived mesenchymal stromal cells (MSCs) in ameliorating experimental asthma. It also demonstrates that not only MSCs present in the pool of BMDMCs are responsible for BMDMCs’ beneficial effects but also monocytes, which are the most important cell population to trigger these effects. All of this is in the setting of a clinically relevant model of severe allergic airways inflammation and thus provides further support for potential clinical use of cell therapy using MSCs, BMDMCs, and also adult cells such as monocytes in patients with severe asthma.