We describe a human nasal epithelial (HNE) organoid model derived directly from patient samples that is well-differentiated and recapitulates the airway epithelium, including the expression of cilia, mucins, tight junctions, the cystic fibrosis transmembrane conductance regulator (CFTR), and ionocytes. This model requires few cells compared to airway epithelial monolayer cultures, with multiple outcome measurements depending on the application. A novel feature of the model is the predictive capacity of lumen formation, a marker of baseline CFTR function that correlates with short-circuit current activation of CFTR in monolayers and discriminates the cystic fibrosis (CF) phenotype from non-CF. Our HNE organoid model is amenable to automated measurements of forskolin-induced swelling (FIS), which distinguishes levels of CFTR activity. While the apical side is not easily accessible, RNA- and DNA-based therapies intended for systemic administration could be evaluated in vitro, or it could be used as an ex vivo biomarker of successful repair of a mutant gene. In conclusion, this highly differentiated airway epithelial model could serve as a surrogate biomarker to assess correction of the mutant gene in CF or other diseases, recapitulating the phenotypic and genotypic diversity of the population.

中文翻译：

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用于囊性纤维化治疗开发的人鼻上皮类器官

我们描述了一种直接源自患者样本的人鼻上皮 (HNE) 类器官模型，该模型具有良好的分化并概括了气道上皮，包括纤毛、粘蛋白、紧密连接、囊性纤维化跨膜电导调节剂 (CFTR) 和离子细胞的表达. 与气道上皮单层培养物相比，该模型需要很少的细胞，根据应用进行多种结果测量。该模型的一个新特征是管腔形成的预测能力，这是基线 CFTR 功能的标记，与单层 CFTR 的短路电流激活相关，并区分囊性纤维化 (CF) 表型与非 CF。我们的 HNE 类器官模型适用于毛喉素诱导肿胀 (FIS) 的自动测量，从而区分 CFTR 活动的水平。虽然顶端一侧不容易获得，但用于全身给药的基于 RNA 和 DNA 的疗法可以在体外进行评估，或者它可以用作成功修复突变基因的离体生物标志物。总之，这种高度分化的气道上皮模型可以作为替代生物标志物来评估 CF 或其他疾病中突变基因的校正，概括人口的表型和基因型多样性。