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.
-
Single-cell RNA-sequencing of human lung Lin-EpCAM+ cellsNCBI Gene Expression Omnibus, GSE157996.
-
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.
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.
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.
Metrics
-
- 1,810
- views
-
- 207
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis
eLife 12:e85415.
https://doi.org/10.7554/eLife.85415
Further reading
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
-
- Cell Biology
G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.
