成为一种成人肺部具有干细胞功能并在损伤后有助于修复的肺泡2型(AT2)细胞。本研究的目的是了解在人类发育过程中控制此种治疗相关细胞类型分化的信号事件。使用肺外植和器官模型，我们确定了TGFβ和BMP信号的对立效应，即在高WNT和FGF信号的背景下，抑制TGFβ信号和激活BMP信号有效地将早期肺祖细胞体外分化成AT2样细胞。以这种方式分化的AT2样细胞具有肺表面活性物质的加工和分泌能力，并在经过原初AT2培养优化的介质中扩增时对成熟AT2表型长期保持承诺。将使用抑制TGFβ和激活BMP分化的AT2样细胞与其他分化方法进行比较显示了改善AT2细胞系的特异性和减少非靶细胞类型。这些发现揭示了TGFβ和BMP信号在AT2分化中的相反作用，并提供了一种在体外产生治疗相关细胞类型的新策略。© 2023. Springer Nature Limited.

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.© 2023. Springer Nature Limited.