Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis

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. Andrian, Steven K. Huang, Roberto F. Nicosia, Maria Trojanowska, Xaralabos Varelas () and Giovanni Ligresti ()
Additional contact information
Ahmed A. Raslan: Boston University Chobanian and Avedisian School of Medicine
Tho X. Pham: Boston University Chobanian and Avedisian School of Medicine
Jisu Lee: Boston University Chobanian and Avedisian School of Medicine
Konstantinos Kontodimas: Boston University Chobanian and Avedisian School of Medicine
Andrew Tilston-Lunel: Boston University Chobanian and Avedisian School of Medicine
Jillian Schmottlach: Boston University Chobanian and Avedisian School of Medicine
Jeongmin Hong: Boston University Chobanian and Avedisian School of Medicine
Taha Dinc: Boston University Chobanian and Avedisian School of Medicine
Andreea M. Bujor: Boston University Chobanian and Avedisian School of Medicine
Nunzia Caporarello: Loyola University Chicago
Aude Thiriot: Harvard Medical School
Ulrich H. Andrian: Harvard Medical School
Steven K. Huang: University of Michigan Medical School
Roberto F. Nicosia: University of Washington
Maria Trojanowska: Boston University Chobanian and Avedisian School of Medicine
Xaralabos Varelas: Boston University Chobanian and Avedisian School of Medicine
Giovanni Ligresti: Boston University Chobanian and Avedisian School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

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.

Date: 2024
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DOI: 10.1038/s41467-024-49545-x

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