Lee Jimmy Tsz Hang, Barnett Sam N, Roberts Kenny, Ashwin Helen, Milross Luke, Cho Jae-Won, Huseynov Alik, Woodhams Benjamin, Aivazidis Alexander, Li Tong, Majo Joaquim, Chaves Patricia, Lee Michael, Miranda Antonio M A, Jablonska Zuzanna, Arena Vincenzo, Hanley Brian, Osborn Michael, Uhlmann Virginie, Xu Xiao-Ning, McLean Gary R, Teichmann Sarah A, Randi Anna M, Filby Andrew, Kaye Paul M, Fisher Andrew J, Hemberg Martin, Noseda Michela, Bayraktar Omer Ali
Wellcome Sanger Institute, Hinxton, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Nat Commun. 2025 Mar 10;16(1):1979. doi: 10.1038/s41467-025-56473-x.
The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.
新型冠状病毒肺炎（COVID-19）导致死亡的最常见原因仍是呼吸衰竭。然而，我们对肺泡损伤背后精确的细胞和分子变化的了解有限。在此，我们将COVID-19和供体肺组织的单细胞转录组数据与对弥漫性肺泡损伤的组织病理学阶段进行分层的空间转录组数据相结合。我们确定了渐进性损伤过程中细胞组成的变化，包括分子特征不同的巨噬细胞浪潮以及上皮和内皮细胞群的耗竭。预测的病理状态标志物确定了免疫调节特征，包括早期损伤中的IFN-α和金属硫蛋白特征，以及晚期损伤中的纤维化相关胶原。此外，我们预测通过内皮细胞上调SERPINE1/PAI-1会导致纤维蛋白溶解停止。细胞间相互作用分析显示，巨噬细胞衍生的SPP1/骨桥蛋白信号传导是肺泡损伤早期阶段的关键调节因子。这些结果提供了一个全面的、空间分辨的COVID-19肺泡损伤进展图谱，突出了重症疾病中促炎和促纤维化途径的细胞机制。
