Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of COPD that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific subpopulation of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single-cell RNA sequencing and in situ localisation revealed that asATII cells co-express the alveolar marker surfactant protein C and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII subpopulation derived from club cells was also identified in mouse COPD models using lineage labelling. Human and mouse ATII subpopulations formed 80–90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies.

肺气肿是肺部气体交换表面的进行性破坏，是目前无法治愈的 COPD 标志。这种治疗差距主要是由于对组织再生受损的潜在驱动因素了解不足，例如异常的肺上皮祖细胞，包括 II 型肺泡 （ATII） 和气道俱乐部细胞。我们发现了一个肺气肿特异性的 ATII 细胞亚群，位于扩大的远端肺泡囊中，称为 ATII 细胞。单细胞 RNA 测序和原位定位显示，asATII 细胞共表达肺泡标志物表面活性剂蛋白 C 和俱乐部细胞标志物分泌珠蛋白-3A2 （SCGB3A2）。使用谱系标记在小鼠 COPD 模型中也鉴定了源自俱乐部细胞的类似 ATII 亚群。与健康对照相比，人和小鼠 ATII 亚群形成的肺泡类器官少 80-90%，表明祖细胞功能降低。靶向 asATII 细胞或其祖细胞俱乐部细胞可以揭示新的 COPD 治疗策略。