Three‐dimensional lung organoids (LOs) derived from pluripotent stem cells have the potential to enhance our understanding of disease mechanisms and to enable novel therapeutic approaches in neonates with pulmonary disorders. We established a reproducible ex vivo model of lung development using transgene‐free human induced pluripotent stem cells generated from fetuses and infants with Bochdalek congenital diaphragmatic hernia (CDH), a polygenic disorder associated with fetal lung compression and pulmonary hypoplasia at birth. Molecular and cellular comparisons of CDH LOs revealed impaired generation of NKX2.1⁺ progenitors, type II alveolar epithelial cells, and PDGFRα⁺ myofibroblasts. We then subjected these LOs to disease relevant mechanical cues through ex vivo compression and observed significant changes in genes associated with pulmonary progenitors, alveolar epithelial cells, and mesenchymal fibroblasts. Collectively, these data suggest both primary cell‐intrinsic and secondary mechanical causes of CDH lung hypoplasia and support the use of this stem cell‐based approach for disease modeling in CDH.

中文翻译：

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先天性膈疝胎肺离体模型中的人诱导多能干细胞衍生的肺类器官。

源自多能干细胞的三维肺类器官（LOs）有可能增强我们对疾病机制的理解，并为患有肺部疾病的新生儿提供新的治疗方法。我们使用从患有 Bochdalek 先天性膈疝 (CDH) 的胎儿和婴儿中产生的无转基因人类诱导多能干细胞建立了可重复的体外肺发育模型，CDH 是一种与出生时胎儿肺受压和肺发育不全相关的多基因疾病。CDH LO 的分子和细胞比较显示 NKX2.1 ⁺祖细胞、II 型肺泡上皮细胞和PDGFRα ^{+的生成受损}肌成纤维细胞。然后，我们通过离体压缩对这些 LO 进行疾病相关的机械提示，并观察到与肺祖细胞、肺泡上皮细胞和间充质成纤维细胞相关的基因的显着变化。总的来说，这些数据表明 CDH 肺发育不全的原发性细胞内在和继发性机械原因，并支持使用这种基于干细胞的方法进行 CDH 疾病建模。