1. Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis
- Author
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Ahmed A. Raslan, Tho X. Pham, Jisu Lee, Konstantinos Kontodimas, Andrew Tilston-Lunel, Jillian Schmottlach, Jeongmin Hong, Taha Dinc, Andreea M. Bujor, Nunzia Caporarello, Aude Thiriot, Ulrich H. von Andrian, Steven K. Huang, Roberto F. Nicosia, Maria Trojanowska, Xaralabos Varelas, and Giovanni Ligresti
- Subjects
Science - Abstract
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.
- Published
- 2024
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