High resolution analysis of heterogeneous alveolar type II cells in emphysema and health reveals an airway origin of impaired alveolar regeneration

Emphysema is a major pathological phenotype of chronic obstructive pulmonary disease (COPD) that is characterized by progressive and irreversible alveolar tissue destruction caused by several stressors, such as tobacco smoke and air pollution. It remains incurable in part due to an incomplete understanding of cellular and molecular mechanisms underlying the failure of tissue repair. Here, we have generated a single cell RNA sequencing dataset of enriched epithelial cells from emphysematous parenchymal lung tissue of COPD patients and from healthy controls. Using this dataset, we performed high resolution analysis of 78,699 ATII cells and reveal novel ATII cell subsets in severe emphysema and health. These include two ATII sub-clusters expressing various secretoglobin mRNAs (SCGBpos) in COPD that present distinct transcriptomic profiles compared to healthy sub-clusters. These ATII sub-clusters that are present in human COPD are also found in a mouse emphysema model. Importantly, the COPD specific ATII cells from both species demonstrate airway origins and fail to undergo alveolar differentiation in organoid cultures, thereby suggesting that a common mechanism in emphysema pathogenesis. Overall design: Single cell RNA-seq profiling of murine COPD model

肺气肿（Emphysema）是慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）的主要病理表型，其特征为烟草烟雾、空气污染等多种应激原引发的进行性、不可逆肺泡组织破坏。由于对组织修复失败背后的细胞与分子机制认识尚不充分，该疾病目前仍无治愈方案。本研究构建了来自COPD患者肺气肿性肺实质组织与健康对照者的富集上皮细胞单细胞RNA测序（single cell RNA sequencing）数据集。利用该数据集，我们对78699个ATII细胞（II型肺泡上皮细胞）开展了高分辨率转录组分析，揭示了重度肺气肿患者与健康个体中存在的新型ATII细胞亚群。研究发现，COPD患者体内存在两类表达多种分泌珠蛋白mRNA的ATII细胞亚簇（SCGBpos），其转录组特征与健康对照亚簇存在显著差异。这类存在于人类COPD患者体内的ATII亚簇，同样可在小鼠肺气肿模型中被检出。尤为关键的是，人类与小鼠体内的COPD特异性ATII细胞均表现出气道起源特征，且在类器官培养中无法完成肺泡分化，这提示肺气肿发病机制中存在保守的共同通路。总体实验设计：小鼠COPD模型的单细胞RNA测序分析。