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- Title
Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis.
- Authors
Raslan, Ahmed A.; Pham, Tho X.; Lee, Jisu; Kontodimas, Konstantinos; Tilston-Lunel, Andrew; Schmottlach, Jillian; Hong, Jeongmin; Dinc, Taha; Bujor, Andreea M.; Caporarello, Nunzia; Thiriot, Aude; von Andrian, Ulrich H.; Huang, Steven K.; Nicosia, Roberto F.; Trojanowska, Maria; Varelas, Xaralabos; Ligresti, Giovanni
- Abstract
Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis. The regenerative capacity of the lung in response to injury deteriorates with aging. Here, Raslan et al. discover that aging-associated progressive lung fibrosis is accompanied by persistent activation of blood vessels. The authors identified the vascular YAP/TrkB axis as a putative driver of this process and potential therapeutic target.
- Subjects
LUNGS; ENDOTHELIAL cells; PULMONARY fibrosis; FIBROSIS; LUNG volume measurements; ENDOTHELIUM diseases
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49545-x