Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

中文翻译：

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囊性纤维化肺部炎症环境对间充质基质细胞的不同影响。


越来越多的证据表明，人间充质基质细胞（MSC）会根据所遇到的特定炎症环境改变其体内抗炎作用。更好地理解这一点对于完善基于间充质干细胞的肺部和其他疾病的细胞疗法至关重要。使用囊性纤维化（CF）肺病急性加重作为模型，体外 MSC 暴露于临床支气管肺泡灌洗液（BALF）样本（作为体内临床肺环境的替代物）对 MSC 活力、基因表达、分泌的细胞因子，并将线粒体功能与从健康志愿者收集的 BALF 的效果进行比较。 CF BALF 样本中曲霉菌培养呈阳性。 (Asp) 会诱导 MSC 快速死亡，通常在暴露后几个小时内发生。进一步的分析表明真菌毒素胶霉毒素是导致 CF BALF 诱导 MSC 死亡的潜在介质。对暴露于 Asp+ 或 Asp- CF BALF 样本的 MSC 进行 RNA 测序分析，发现了许多差异表达的转录本，包括那些与干扰素信号传导、抗微生物基因表达和细胞死亡有关的转录本。毒性与细菌性肺部感染无关。这些结果表明，在曲霉菌存在的情况下，可能无法保证使用基于 MSC 的细胞疗法治疗 CF 或其他肺部疾病。