Human PSC-based Modeling of Pulmonary Fibrosis Identifies p300/CBP Inhibition as a Suppressor of Alveolar Transitional Cell State [BLM]

In this study, we conducted a drug screening using an in vitro pulmonary fibrosis model and identified p300/CBP inhibitors as candidate therapeutic agents. We investigated the mechanisms underlying the emergence of the alveolar transitional cell state (ATCS) with human PSC-derived alveolar organoids. Overall design: Alveolar organoids composed of SPC-GFP reporter iPSC line (B2-3)-derived alveolar epithelial type 2 (AT2) cells and human fetal lung fibroblasts (HFLFs) were treated with DMSO or BLM for 3 days , followed by an additional 3-day incubation with or without compounds. For gene expression profile analysis, HFLFs were isolated from the organoids through magnetic activated cell sorting using anti-EpCAM antibody.

本研究通过体外肺纤维化模型开展药物筛选，鉴定出p300/CBP抑制剂作为候选治疗药物。我们利用人源多能干细胞（PSC）来源的肺泡类器官，探究了肺泡过渡细胞状态（ATCS）的产生机制。总体实验设计：以携带SPC-GFP报告基因的诱导多能干细胞（iPSC）系（B2-3）来源的肺泡Ⅱ型上皮细胞（AT2）与人类胎肺成纤维细胞（HFLFs）构建肺泡类器官，将其用二甲基亚砜（DMSO）或博莱霉素（BLM）处理3天，随后在有无化合物干预的条件下继续培养3天。针对基因表达谱分析，我们通过抗EpCAM抗体进行磁激活细胞分选，从类器官中分离得到HFLFs。