Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis
Jiurong Liang,
Guanling Huang,
Xue Liu,
Ningshan Liu,
Forough Taghavifar,
Kristy Dai,
Changfu Yao,
Nan Deng,
Yizhou Wang,
Peter Chen,
Cory Hogaboam,
Barry R Stripp,
William C Parks,
Paul W Noble,
Dianhua Jiang
Affiliations
Jiurong Liang
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Guanling Huang
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Xue Liu
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Ningshan Liu
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Forough Taghavifar
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Kristy Dai
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Changfu Yao
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Nan Deng
Genomics Core, Cedars-Sinai Medical Center, los Angeles, United States
Yizhou Wang
Genomics Core, Cedars-Sinai Medical Center, los Angeles, United States
Peter Chen
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Cory Hogaboam
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Barry R Stripp
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
William C Parks
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States
Paul W Noble
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States
Department of Medicine and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, United States; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States
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.
