Aubert Ophelia, Miyake Yuichiro, Amonkar Gaurang M, Dinwoodie Olivia M, Varisco Brian M, Marotta Mario, Zhao Caiqi, Wagner Richard, Chen Ya-Wen, Moscatello Alessandra, Tiozzo Caterina, Varelas Xaralabos, Lerou Paul H, Peiro Jose L, Keijzer Richard, Ai Xingbin
Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany.
Am J Respir Cell Mol Biol. 2025 Jun;72(6):688-697. doi: 10.1165/rcmb.2024-0323OC.
Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. Although the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model, and a nitrofen rat model, we investigated whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more alveolar epithelial type II (ATII) cells, fewer ATI cells, and the emergence of cells coexpressing ATI and ATII markers. Associated with these alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced YAP and abnormal distal lung development were evident as early as 21 weeks of gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and more abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. Tracheal occlusion can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention.
先天性膈疝（CDH）的特征是膈肌闭合不全。尽管由此对胎儿肺部造成的压迫会导致肺发育不全，但CDH中肺泡上皮细胞的特定细胞表型和发育信号缺陷尚未完全明确。我们利用人类CDH的肺样本、手术羔羊模型和硝呋太尔大鼠模型，研究了肺部压迫是否会损害肺泡上皮分化以及Yes相关蛋白（YAP）介导的机械传感。我们发现，人类和羔羊的CDH导致肺泡上皮分化缺陷，表现为肺泡II型上皮（ATII）细胞增多、I型上皮（ATI）细胞减少，以及同时表达ATI和ATII标志物的细胞出现。与这些肺泡上皮缺陷相关，我们发现YAP的水平和核定位降低。在人类CDH中，早在妊娠21周时就明显出现YAP减少和远端肺发育异常。此外，患有CDH的大鼠胎儿也表现出核YAP减少和ATII细胞增多。相比之下，没有疝气的同窝仔没有这种肺泡表型。此外，在CDH手术羔羊模型中进行胎儿气管闭塞可使核YAP完全恢复正常，并以依赖于胎龄的方式挽救肺泡上皮缺陷。综上所述，我们跨物种的研究结果表明，CDH中的肺部压迫足以破坏肺泡上皮分化并损害YAP信号传导。气管闭塞可以恢复核YAP并挽救CDH中的肺泡缺陷，这取决于这种产前手术干预的时机和持续时间。
