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

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  • Ahmed A. Raslan

    (Boston University Chobanian and Avedisian School of Medicine
    Boston University Chobanian and Avedisian School of Medicine
    Faculty of Science, Assiut University)

  • Tho X. Pham

    (Boston University Chobanian and Avedisian School of Medicine
    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
    Boston University Chobanian and Avedisian School of Medicine)

  • Andrew Tilston-Lunel

    (Boston University Chobanian and Avedisian School of Medicine
    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
    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
    MIT and Harvard)

  • Steven K. Huang

    (University of Michigan Medical School)

  • Roberto F. Nicosia

    (University of Washington)

  • Maria Trojanowska

    (Boston University Chobanian and Avedisian School of Medicine
    Boston University Chobanian and Avedisian School of Medicine)

  • Xaralabos Varelas

    (Boston University Chobanian and Avedisian School of Medicine
    Boston University Chobanian and Avedisian School of Medicine)

  • Giovanni Ligresti

    (Boston University Chobanian and Avedisian School of Medicine
    Boston University Chobanian and Avedisian School of Medicine)

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.

Suggested Citation

  • 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 & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49545-x
    DOI: 10.1038/s41467-024-49545-x
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