Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture
Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture
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DOI：
10.1038/labinvest.2015.114
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发表时间：
2015-12-01
影响因子：
5
通讯作者：
Magnusson, Magnus K.
中科院分区：
文献类型：
--
作者：
Jonsdottir, Hulda R.;Arason, Ari J.;Magnusson, Magnus K.
特发性肺纤维化（IPF）是一种进行性肺间质性疾病，发病率和死亡率高。纤维化过程的细胞来源目前正在争论中，其中一种建议的机制是肺泡区域的上皮细胞向间质细胞转化（EMT）。在这项研究中，我们发现在IPF中覆盖成纤维细胞病灶的气道上皮包含一层p63阳性基底细胞，而缺乏纤毛和杯状细胞。该基底上皮显示CK14、波形蛋白和N-钙粘蛋白的表达增加，同时保留E-钙粘蛋白。下面的成纤维细胞灶显示E-和N-钙粘蛋白阳性细胞。为了确定p63阳性基底细胞是否能够在培养物中经历EMT，我们用血清替代品UltroserG处理p63阳性基底细胞系VA 10。处理的细胞的亚群获得间质表型，包括E-到N-钙粘蛋白开关。分离后，这些细胞表现出EMT的主要特征（上皮标志物丢失，间充质标志物获得，迁移增加和锚定非依赖性生长）。这种表型转换在p63敲低（KD）细胞中被阻止。总之，我们发现，覆盖在IPF成纤维细胞病灶上的气道上皮细胞缺乏其特征性的功能特性，显示出基底细胞的反应性增加和部分EMT表型的获得。这项研究表明，一些p63阳性的基底细胞易于发生表型变化，并可能在IPF中充当EMT祖细胞。
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high morbidity and mortality. The cellular source of the fibrotic process is currently under debate with one suggested mechanism being epithelial-to-mesenchymal transition (EMT) in the alveolar region. In this study, we show that airway epithelium overlying fibroblastic foci in IPF contains a layer of p63-positive basal cells while lacking ciliated and goblet cells. This basal epithelium shows increased expression of CK14, Vimentin and N-cadherin while retaining E-cadherin. The underlying fibroblastic foci shows both E- and N-cadherin-positive cells. To determine if p63-positive basal cells were able to undergo EMT in culture, we treated VA10, a p63-positive basal cell line, with the serum replacement UltroserG. A sub-population of treated cells acquired a mesenchynnal phenotype, including an E- to N-cadherin switch. After isolation, these cells portrayed a phenotype presenting major hallmarks of EMT (loss of epithelial markers, gain of mesenchymal markers, increased migration and anchorage-independent growth). This phenotypic switch was prevented in p63 knockdown (KD) cells. In conclusion, we show that airway epithelium overlying fibroblastic foci in IPF lacks its characteristic functional identity, shows increased reactivity of basal cells and acquisition of a partial EMT phenotype. This study suggests that some p63-positive basal cells are prone to phenotypic changes and could act as EMT progenitors in IPF.