Spatial map of the lung reveals cellular mechanisms driving damage and fibrosis in severe COVID-19
A lung affected by deadly forms of COVID-19 not only loses essential cells for breathing but also undergoes profound changes in its internal organization and the way its cells communicate with each other. A study involving the Sant Pau Research Institute (IR Sant Pau), published in Nature Communications, has created a spatial map of this transformation and identified some of the molecular…
A comprehensive spatial map of the lung affected by severe COVID-19 has been created, revealing the cellular mechanisms that drive damage and fibrosis. Led by Dr. Manel Esteller from the Sant Pau Research Institute, the study analyzed lung tissue from 19 COVID-19 patients, seven with acute diffuse alveolar damage (DAD) and 12 with proliferative DAD, alongside control samples.
The research utilized spatial transcriptomics, preserving tissue organization and allowing gene expression to be linked to the lung's architecture. Key findings include a loss of essential cells like alveolar type 1 pneumocytes (AT1) and an increase in type 2 pneumocytes (AT2), particularly in proliferative DAD. Capillary endothelial cells and natural killer cells are lost, while macrophages and peribronchial fibroblasts increase.
The fibroblasts reorganize to form specific niches, contributing to fibrosis. Spatial analysis identified a communication signature associated with proliferative DAD, linked to the transforming growth factor beta (TGF-β) pathway. An imbalance in the TGF-β signaling, with increased SMAD3 activity and decreased SMAD7, drives this fibrotic response.
The TIMP1-CD63 interaction also plays a significant role. Despite intense fibrosis, the lung attempts to repair the damaged alveolar epithelium, with type 2 pneumocytes differentiating into type 1 cells in some regions. Understanding these mechanisms could lead to targeted therapies to limit pulmonary fibrosis.
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