Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified the transcription factor Klf5 as an essential determinant of alveolar epithelial cell fate across the lifespan. We show that although dispensable for both adult alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 enforces AT1 cell lineage fidelity during development. Using infectious and non-infectious models of acute respiratory distress syndrome, we demonstrate that Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner during lung regeneration. Moreover, ex vivo organoid assays identify that Klf5 reduces AT2 cell sensitivity to inflammatory signaling to drive AT2-AT1 cell differentiation. These data define the roll of a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.

肺泡上皮细胞命运决定驱动肺发育和再生。使用转录组和表观遗传分析以及遗传小鼠和类器官模型，我们确定转录因子 Klf5 是肺泡上皮细胞在整个生命周期中命运的重要决定因素。我们表明，虽然对于成人肺泡上皮 1 型 (AT1) 和肺泡上皮 2 型 (AT2) 细胞稳态来说都是可有可无的，但 Klf5 在发育过程中强制 AT1 细胞谱系保真度。使用急性呼吸窘迫综合征的感染性和非感染性模型，我们证明 Klf5 在肺再生过程中以空间受限的方式抑制 AT2 细胞增殖并增强 AT2-AT1 细胞分化。此外，离体类器官分析发现 Klf5 降低了 AT2 细胞对炎症信号传导的敏感性，从而驱动 AT2-AT1 细胞分化。这些数据定义了 AT1 细胞谱系定型和 AT2 细胞在肺再生过程中对炎症串扰的反应的主要转录调节因子的滚动。