Duong Thu Elizabeth, Diep Dinh, Conklin Kimberly Y, Bui Indy, Purkerson Jeffrey M, Boone Eric, Olness Jacqueline, Patel Sahil, Peng Beverly, Kern Colin, Zhao Zoey, Misra Ravi S, Huyck Heidie L, Verheyden Jamie M, Borok Zea, Zhang Yun, Scheuermann Richard H, Zhu Quan, Deutsch Gail, Hagood James, Sun Xin, Zhang Kun, Pryhuber Gloria S
Department of Pediatrics, University of California San Diego, La Jolla, CA.
Department of Bioengineering, University of California San Diego, La Jolla, CA.
bioRxiv. 2025 May 23:2025.05.23.655666. doi: 10.1101/2025.05.23.655666.
Developing high-resolution reference maps of disease-susceptible spatial niches is a critical step to mitigating the profound effects of lung disease. Here, we present an integrated multimodal single-nucleus human lung atlas (snHLA) profiling 746,047 nuclei from 49 mapped lung blocks spanning clinically relevant distal airways, alveoli, and interstitium across 11 healthy adults. Integrating snRNA-seq and SNARE-seq2, which co-assays chromatin accessibility and gene expression from the same nucleus, we resolved 70 molecularly distinct populations and captured 332,846 accessible chromatin regions, nominating new transcriptional regulators of human lung cell diversity. Spatial transcriptomics using MERFISH mapped 25 cell populations across 7 structural neighborhoods and multiplexed immunofluorescence localized cell subtypes and distal airway-defining protein markers, expanding and validating distinct lung structure-specific cell populations. This open access snHLA and companion Cell Type and Marker Gene Dictionary with anatomically aligned nomenclature delivers a foundational resource at an unprecedented resolution to interrogate the origins of lung pathophysiology.
绘制疾病易感性空间生态位的高分辨率参考图谱是减轻肺部疾病深远影响的关键一步。在此，我们展示了一个整合的多模态单核人类肺图谱（snHLA），对来自11名健康成年人的49个映射肺组织块中的746,047个细胞核进行了分析，这些组织块涵盖了临床相关的远端气道、肺泡和间质。整合snRNA-seq和SNARE-seq2（可同时检测同一细胞核中的染色质可及性和基因表达），我们解析出70个分子上不同的细胞群，并捕获了332,846个可及染色质区域，确定了人类肺细胞多样性的新转录调节因子。使用MERFISH的空间转录组学绘制了7个结构区域的25个细胞群，多重免疫荧光定位了细胞亚型和远端气道定义蛋白标记物，扩展并验证了不同的肺结构特异性细胞群。这个开放获取的snHLA以及配套的具有解剖学对齐命名法的细胞类型和标记基因词典以前所未有的分辨率提供了一个基础资源，用于探究肺病理生理学的起源。
