Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies
Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies
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DOI：
10.1172/jci.insight.99385
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发表时间：
2018-07-12
期刊：
影响因子：
8
通讯作者：
Clancy, John P.
中科院分区：
文献类型：
--
作者：
Brewington, John J.;Filbrandt, Erin T.;Clancy, John P.
囊性纤维化（CF）治疗的最新进展靶向CF跨膜传导调节因子（CFTR）蛋白的潜在缺陷，但疗效分析仍限于特定基因型亚组。因此，患者衍生的模型系统可能有助于扩大这些药物的可及性。刷过的人鼻上皮细胞（HNE）是一种有吸引力的组织来源，但仍不清楚它们如何忠实地再现人支气管上皮细胞（HBE）CFTR活性。我们使用在空气-液体界面培养的具有各种CFTR突变的儿科CF受试者的成对刷取HNE/HBE样本来检查这种差距。两种细胞类型的生长和结构特征相似，包括分化为成熟的呼吸道上皮细胞。在电生理学分析中，鼻和支气管培养物在基线电阻或上皮钠通道（ENaC）活性方面没有发现相关性。相反，在刺激和抑制CFTR活性方面，鼻和支气管培养物之间表现出强相关性。在CFTR活性的调节剂诱导的变化有密切的相关性，和CFTR活性在两种细胞类型与体内汗液氯离子测量。这些数据证实，刷取的HNE细胞培养物忠实地再现了HBE的功能性CFTR特征，因此是用于个体化CFTR分析的适当的非侵入性HBE替代物。
Recent advances in the management of cystic fibrosis (CF) target underlying defects in the CF transmembrane conductance regulator (CFTR) protein, but efficacy analyses remain limited to specific genotype-based subgroups. Patient-derived model systems may therefore aid in expanding access to these drugs. Brushed human nasal epithelial cells (HNEs) are an attractive tissue source, but it remains unclear how faithfully they recapitulate human bronchial epithelial cell (HBE) CFTR activity. We examined this gap using paired, brushed HNE/HBE samples from pediatric CF subjects with a wide variety of CFTR mutations cultured at the air-liquid interface. Growth and structural characteristics for the two cell types were similar, including differentiation into mature respiratory epithelia. In electrophysiologic analysis, no correlation was identified between nasal and bronchial cultures in baseline resistance or epithelial sodium channel (ENaC) activity. Conversely, robust correlation was demonstrated between nasal and bronchial cultures in both stimulated and inhibited CFTR activity. There was close correlation in modulator-induced change in CFTR activity, and CFTR activity in both cell types correlated with in vivo sweat chloride measurements. These data confirm that brushed HNE cell cultures recapitulate the functional CFTR characteristics of HBEs with fidelity and are therefore an appropriate noninvasive HBE surrogate for individualized CFTR analysis.