人类远端肺图和谱系层次揭示了一个双能祖细胞

SCI

15 April 2022

Human distal lung maps and lineage hierarchies reveal a bipotent progenitor

(NATURE ; IF:49.962)

• Kadur Lakshminarasimha Murthy P, Sontake V, Tata A, et al. Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature 2022;604(7904):111-119. (In eng). DOI: 10.1038/s41586-022-04541-3.

• CORRESPONDENCE TO: purushothamarao.tata@duke.edu

Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not—to our knowledge—been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5–7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease

      绘制构成细胞的空间分布和分子特性对于理解健康和疾病中的组织动力学至关重要。我们缺乏一份全面的人类远端气道地图，包括末端和呼吸性细支气管(TRBs),它们与呼吸疾病有关。在这里，利用空间转录组学和显微解剖远端气道的单细胞分析，他们确定了分子上不同的末端和呼吸细支气管 (TRB)细胞类型，这些细胞类型以前没有被表征过。这些包括气道相关的 LGR5+ 成纤维细胞和 TRB 特异性肺泡 0 型 (AT0) 细胞和 TRB 分泌细胞 (TRB-SCs)。连接组图和基于类器官的共培养表明 LGR5+ 成纤维细胞在气道生态位中形成了一个信号枢纽。AT0细胞和TRB-SCs在灵长类动物中是保守的，在人类肺发育过程中是动态出现的。利用非人灵长类肺损伤模型，结合人体器官和组织标本，研究人员发现再生肺中的肺泡2型细胞会短暂获得AT0状态，从该状态可以分化为肺泡1型细胞或TRB-SCs。这种分化程序不同于在小鼠肺中确定的分化程序。我们的研究还揭示了双能力AT0细胞分化为正常或病理状态的机制。总之，我们的发现修正了人类肺细胞图谱和谱系轨迹，并暗示了灵长类肺再生和疾病中的上皮过渡状态。