IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49545-x.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49545-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-49545-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Nunzia Caporarello & Jisu Lee & Tho X. Pham & Dakota L. Jones & Jiazhen Guan & Patrick A. Link & Jeffrey A. Meridew & Grace Marden & Takashi Yamashita & Collin A. Osborne & Aditya V. Bhagwate & Steven, 2022. "Author Correction: Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    2. Ilias Angelidis & Lukas M. Simon & Isis E. Fernandez & Maximilian Strunz & Christoph H. Mayr & Flavia R. Greiffo & George Tsitsiridis & Meshal Ansari & Elisabeth Graf & Tim-Matthias Strom & Monica Nag, 2019. "An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    3. Maximilian Strunz & Lukas M. Simon & Meshal Ansari & Jaymin J. Kathiriya & Ilias Angelidis & Christoph H. Mayr & George Tsidiridis & Marius Lange & Laura F. Mattner & Min Yee & Paulina Ogar & Arunima , 2020. "Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    4. Nathaniel Kastan & Ksenia Gnedeva & Theresa Alisch & Aleksandra A. Petelski & David J. Huggins & Jeanne Chiaravalli & Alla Aharanov & Avraham Shakked & Eldad Tzahor & Aaron Nagiel & Neil Segil & A. J., 2021. "Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    5. Neil P. Dufton & Claire R. Peghaire & Lourdes Osuna-Almagro & Claudio Raimondi & Viktoria Kalna & Abhishek Chauhan & Gwilym Webb & Youwen Yang & Graeme M. Birdsey & Patricia Lalor & Justin C. Mason & , 2017. "Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    6. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
    7. Nunzia Caporarello & Jisu Lee & Tho X. Pham & Dakota L. Jones & Jiazhen Guan & Patrick A. Link & Jeffrey A. Meridew & Grace Marden & Takashi Yamashita & Collin A. Osborne & Aditya V. Bhagwate & Steven, 2022. "Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Di-Yang Sun & Wen-Bin Wu & Jian-Jin Wu & Yu Shi & Jia-Jun Xu & Shen-Xi Ouyang & Chen Chi & Yi Shi & Qing-Xin Ji & Jin-Hao Miao & Jiang-Tao Fu & Jie Tong & Ping-Ping Zhang & Jia-Bao Zhang & Zhi-Yong Li, 2024. "Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Sandra Curras-Alonso & Juliette Soulier & Thomas Defard & Christian Weber & Sophie Heinrich & Hugo Laporte & Sophie Leboucher & Sonia Lameiras & Marie Dutreix & Vincent Favaudon & Florian Massip & Tho, 2023. "An interactive murine single-cell atlas of the lung responses to radiation injury," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Nunzia Caporarello & Jisu Lee & Tho X. Pham & Dakota L. Jones & Jiazhen Guan & Patrick A. Link & Jeffrey A. Meridew & Grace Marden & Takashi Yamashita & Collin A. Osborne & Aditya V. Bhagwate & Steven, 2022. "Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Christopher W. Murray & Jennifer J. Brady & Mingqi Han & Hongchen Cai & Min K. Tsai & Sarah E. Pierce & Ran Cheng & Janos Demeter & David M. Feldser & Peter K. Jackson & David B. Shackelford & Monte M, 2022. "LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    6. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Seoyeon Lee & Mohammad Naimul Islam & Kaveh Boostanpour & Dvir Aran & Guangchun Jin & Stephanie Christenson & Michael A. Matthay & Walter L. Eckalbar & Daryle J. DePianto & Joseph R. Arron & Liam Mage, 2021. "Molecular programs of fibrotic change in aging human lung," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    8. Andrea Toth & Paranthaman Kannan & John Snowball & Matthew Kofron & Joseph A. Wayman & James P. Bridges & Emily R. Miraldi & Daniel Swarr & William J. Zacharias, 2023. "Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    9. Jianxin Shi & Kouya Shiraishi & Jiyeon Choi & Keitaro Matsuo & Tzu-Yu Chen & Juncheng Dai & Rayjean J. Hung & Kexin Chen & Xiao-Ou Shu & Young Tae Kim & Maria Teresa Landi & Dongxin Lin & Wei Zheng & , 2023. "Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Xin Pan & Lan Wang & Juntang Yang & Yingge Li & Min Xu & Chenxi Liang & Lulu Liu & Zhongzheng Li & Cong Xia & Jiaojiao Pang & Mengyuan Wang & Meng Li & Saiya Guo & Peishuo Yan & Chen Ding & Ivan O. Ro, 2024. "TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    11. Yu Wang & Zhi-Ying Guan & Shao-Wen Shi & Yi-Rong Jiang & Jie Zhang & Yi Yang & Qiong Wu & Jie Wu & Jian-Bo Chen & Wei-Xin Ying & Qin-Qin Xu & Qian-Xi Fan & Hui-Feng Wang & Li Zhou & Ling Wang & Jin Fa, 2024. "Pick-up single-cell proteomic analysis for quantifying up to 3000 proteins in a Mammalian cell," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Aleksandr Ianevski & Anil K. Giri & Tero Aittokallio, 2022. "Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    13. Gan Zhao & Maria E. Gentile & Lulu Xue & Christopher V. Cosgriff & Aaron I. Weiner & Stephanie Adams-Tzivelekidis & Joanna Wong & Xinyuan Li & Sara Kass-Gergi & Nicolas P. Holcomb & Maria C. Basal & K, 2024. "Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Zhoufeng Wang & Zhe Li & Kun Zhou & Chengdi Wang & Lili Jiang & Li Zhang & Ying Yang & Wenxin Luo & Wenliang Qiao & Gang Wang & Yinyun Ni & Shuiping Dai & Tingting Guo & Guiyi Ji & Minjie Xu & Yiying , 2021. "Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    15. Laura Heydemann & Małgorzata Ciurkiewicz & Georg Beythien & Kathrin Becker & Klaus Schughart & Stephanie Stanelle-Bertram & Berfin Schaumburg & Nancy Mounogou-Kouassi & Sebastian Beck & Martin Zickler, 2023. "Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Lucy Xia & Christy Lee & Jingyi Jessica Li, 2024. "Statistical method scDEED for detecting dubious 2D single-cell embeddings and optimizing t-SNE and UMAP hyperparameters," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    17. Marc A. Vittoria & Nathan Kingston & Kristyna Kotynkova & Eric Xia & Rui Hong & Lee Huang & Shayna McDonald & Andrew Tilston-Lunel & Revati Darp & Joshua D. Campbell & Deborah Lang & Xiaowei Xu & Crai, 2022. "Inactivation of the Hippo tumor suppressor pathway promotes melanoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    18. Birthe Dorgau & Joseph Collin & Agata Rozanska & Darin Zerti & Adrienne Unsworth & Moira Crosier & Rafiqul Hussain & Jonathan Coxhead & Tamil Dhanaseelan & Aara Patel & Jane C. Sowden & David R. FitzP, 2024. "Single-cell analyses reveal transient retinal progenitor cells in the ciliary margin of developing human retina," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Dalia Hassan & Jichao Chen, 2024. "CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Benjamin Ng & Kevin Y. Huang & Chee Jian Pua & Sivakumar Viswanathan & Wei-Wen Lim & Fathima F. Kuthubudeen & Yu-Ning Liu & An An Hii & Benjamin L. George & Anissa A. Widjaja & Enrico Petretto & Stuar, 2024. "Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49545-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.