Slug/Snail2 belongs to the Epithelial-Mesenchymal Transition (EMT)-inducing transcription factors involved in development and diseases. Slug is expressed in adult stem/progenitor cells of several epithelia, making it unique among these transcription factors. To investigate Slug role in human bronchial epithelium progenitors, we studied primary bronchial basal/progenitor cells in an air-liquid interface culture system that allows regenerating a bronchial epithelium. To identify Slug downstream genes we knocked down Slug in basal/progenitor cells from normal subjects and subjects with COPD, a respiratory disease presenting anomalies in the bronchial epithelium and high levels of TGF-β in the lungs. We show that normal and COPD bronchial basal/progenitors, even when treated with TGF-β, express both epithelial and mesenchymal markers, and that the epithelial marker E-cadherin is not a target of Slug and, moreover, positively correlates with Slug. We reveal that Slug downstream genes responding to both differentiation and TGF-β are different in normal and COPD progenitors, with in particular a set of proliferation-related genes that are among the genes repressed downstream of Slug in normal but not COPD. In COPD progenitors at the onset of differentiation in presence of TGF-β,we show that there is positive correlations between the effect of differentiation and TGF-β on proliferation-related genes and on Slug protein, and that their expression levels are higher than in normal cells. As well, the expression of Smad3 and β-Catenin, two molecules from TGF-βsignaling pathways, are higher in COPD progenitors, and our results indicate that proliferation-related genes and Slug protein are increased by different TGF-β-induced mechanisms.

Graphical abstract

中文翻译：

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TGF-β 抑制的增殖基因位于正常支气管上皮祖细胞中 Slug/Snail2 的下游，并且在 COPD 中失调

Slug/Snail2 属于上皮间质转化 (EMT) 诱导转录因子，参与发育和疾病。Slug 在几种上皮细胞的成体干/祖细胞中表达，使其在这些转录因子中独一无二。为了研究蛞蝓在人支气管上皮祖细胞中的作用，我们研究了气-液界面培养系统中的原代支气管基底/祖细胞，该系统允许再生支气管上皮。为了识别 Slug 下游基因，我们在正常受试者和 COPD 受试者的基底/祖细胞中敲除 Slug，COPD 是一种呼吸道疾病，表现为支气管上皮异常和肺部高水平的 TGF-β。我们表明，即使用 TGF-β 治疗，正常和 COPD 支气管基底/祖细胞也表达上皮和间充质标志物，并且上皮标志物 E-cadherin 不是 Slug 的靶标，而且与 Slug 呈正相关。我们揭示，在正常和 COPD 祖细胞中，对分化和 TGF-β 作出反应的 Slug 下游基因是不同的，特别是一组增殖相关基因，它们在正常情况下在 Slug 下游被抑制但不是 COPD 的基因中。在 TGF-β 存在下分化开始的 COPD 祖细胞中，我们发现分化与 TGF-β 对增殖相关基因和 Slug 蛋白的影响之间存在正相关，并且它们的表达水平高于在正常细胞。同样，来自 TGF-β 信号通路的两个分子 Smad3 和 β-Catenin 在 COPD 祖细胞中的表达更高，

图形概要