Alveolar type 2 (AT2) epithelial cells are tissue stem cells capable of differentiating into alveolar type 1 (AT1) cells for injury repair and maintenance of lung homeostasis. However, the factors involved in human AT2-to-AT1 cell differentiation are not fully understood. Here, we established and dual-reporter induced pluripotent stem cells (iPSCs), which detected AT2-to-AT1 cell differentiation with high sensitivity and identified factors inducing AT1 cell differentiation from AT2 and their progenitor cells. We also established an “on-gel” alveolar epithelial spheroid culture suitable for medium-throughput screening. Among the 274 chemical compounds, several single compounds, including LATS-IN-1, converted AT1 cells from AT2 and their progenitor cells. Moreover, YAP/TAZ signaling activation and AKT signaling suppression synergistically recapitulated the induction of transcriptomic, morphological, and functionally mature AT1 cells. Our findings provide novel insights into human lung development and lung regenerative medicine.

中文翻译：

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利用人多能干细胞筛选肺泡1型上皮细胞诱导因子

肺泡 2 型 (AT2) 上皮细胞是能够分化为肺泡 1 型 (AT1) 细胞的组织干细胞，用于损伤修复和维持肺稳态。然而，参与人类 AT2 至 AT1 细胞分化的因素尚不完全清楚。在这里，我们建立了双报告基因诱导的多能干细胞（iPSC），它能够高灵敏度地检测 AT2 向 AT1 细胞的分化，并鉴定出诱导 AT1 细胞从 AT2 及其祖细胞分化的因子。我们还建立了适合中等通量筛选的“凝胶上”肺泡上皮球体培养物。在 274 种化合物中，包括 LATS-IN-1 在内的几种单一化合物可将 AT2 细胞及其祖细胞转变为 AT1 细胞。此外，YAP/TAZ 信号传导激活和 AKT 信号传导抑制协同概括了转录组、形态学和功能成熟 AT1 细胞的诱导。我们的研究结果为人类肺部发育和肺再生医学提供了新的见解。