Hu Yan, Hu Qianjiang, Ansari Meshal, Riemondy Kent, Pineda Ricardo, Sembrat John, Leme Adriana S, Ngo Kenny, Morgenthaler Olivia, Ha Kellie, Gao Bifeng, Janssen William J, Basil Maria C, Kliment Corrine R, Morrisey Edward, Lehmann Mareike, Evans Christopher M, Schiller Herbert B, Königshoff Melanie
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Center for Lung Aging and Regeneration (CLAR), Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Eur Respir J. 2024 Dec 5;64(6). doi: 10.1183/13993003.02071-2023. Print 2024 Dec.
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 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，是慢性阻塞性肺疾病（COPD）的一个标志，目前无法治愈。这种治疗差距很大程度上是由于对组织再生受损的潜在驱动因素了解不足，比如异常的肺上皮祖细胞，包括肺泡II型（ATII）细胞和气道俱乐部细胞。我们发现了位于扩大的远端肺泡囊中的ATII细胞的肺气肿特异性亚群，称为asATII细胞。单细胞RNA测序和定位显示，asATII细胞共表达肺泡标志物表面活性蛋白C和俱乐部细胞标志物分泌球蛋白-3A2（SCGB3A2）。在小鼠慢性阻塞性肺疾病模型中，使用谱系标记也鉴定出了源自俱乐部细胞的类似ATII亚群。与健康对照相比，人和小鼠的ATII亚群形成的肺泡类器官减少了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能会揭示慢性阻塞性肺疾病的新治疗策略。
