Accurate fluid pressure in the fetal lung is critical for its development, especially at the beginning of the saccular stage when alveolar epithelial type 1 (AT1) and type 2 (AT2) cells differentiate from the epithelial progenitors. Despite our growing understanding of the role of physical forces in lung development, the molecular mechanisms that regulate the transduction of mechanical stretch to alveolar differentiation remain elusive. To simulate lung distension, we optimized both an ex vivo model with precision cut lung slices and an in vivo model of fetal tracheal occlusion. Increased mechanical tension showed to improve alveolar maturation and differentiation towards AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation towards AT1 phenotype via ROCK activity. Our findings show that balanced ROCK-Yap/Taz signaling is essential to regulate AT1 differentiation in response to mechanical stretching of the fetal lung, which might be helpful in improving lung development and regeneration.

中文翻译：

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拉伸通过 ROCK-Yap/Taz 通路增加胎儿肺中的肺泡 1 型细胞数量

胎肺中准确的流体压力对其发育至关重要，尤其是在囊状阶段开始时，此时肺泡上皮 1 型 (AT1) 和 2 型 (AT2) 细胞与上皮祖细胞分化。尽管我们越来越了解物理力在肺发育中的作用，但调节机械拉伸到肺泡分化的转导的分子机制仍然难以捉摸。为了模拟肺扩张，我们优化了具有精确切割肺切片的离体模型和胎儿气管闭塞的体内模型。增加的机械张力显示出改善肺泡成熟和向 AT1 的分化。通过操纵 ROCK 通路，我们证明拉伸诱导的 Yap/Taz 激活通过 ROCK 活性促进肺泡向 AT1 表型分化。