Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis
- Cedars-Sinai Medical Center, United States
Abstract
Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.
Data availability
The raw datasets of single cell RNA-seq of mouse and human epithelial cells are under GSE157995 and GSE157996, respectively.
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Single-cell RNA-sequencing of human lung Lin-EpCAM+ cellsNCBI Gene Expression Omnibus, GSE157996.
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Single-cell RNA-sequencing of mouse and human lung Lin-EpCAM+ cellsNCBI Gene Expression Omnibus, GSE157997.
Article and author information
Author details
Funding
National Institute on Aging (R0-1AG078655)
- jiurong Liang
National Heart, Lung, and Blood Institute (R35-HL150829)
- Paul W Noble
National Heart, Lung, and Blood Institute (R01-HL060539)
- Paul W Noble
National Heart, Lung, and Blood Institute (P01-HL108793)
- Dianhua Jiang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Monica Kraft, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: Animals and Study ApprovalAll mouse maintenance and procedures were done under the guidance of the Cedars-Sinai Medical Center Institutional Animal Care and Use Committee (IACUC008529) in accordance with institutional and regulatory guidelines. All mice were housed in a pathogen-free facility at Cedars-Sinai. Eight to 12 weeks old (young) and 18 to 24 months old (aged) wild-type C57Bl/6J mice were obtained from The Jackson Laboratory and housed in the institution facility at least 2 weeks before experiments.
Human subjects: Information of human subjects, Human Lung Tissue, and Study ApprovalThe use of human tissues for research was approved by the Institutional Review Board (IRB) of Cedars-Sinai and was under the guidelines outlined by the IRB (Pro00032727). Informed consent was obtained from each subject. The human samples used in the studies are age matched between IPF and healthy donors. The median age is 60 for healthy donors and 66 for IPF patients. We are aware to get the best age-matched samples within each experiment.
Version history
- Preprint posted: July 30, 2020 (view preprint)
- Received: December 7, 2022
- Accepted: June 13, 2023
- Accepted Manuscript published: June 14, 2023 (version 1)
- Version of Record published: June 26, 2023 (version 2)
Copyright
© 2023, Liang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis
eLife 12:e85415.
https://doi.org/10.7554/eLife.85415
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