Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir
Chaoqun Wang, Ben Hyams, Nancy C. Allen, Kelly Cautivo, Kiara Monahan, Minqi Zhou, Madelene W. Dahlgren, Carlos O. Lizama, Michael Matthay, Paul Wolters, Ari B. Molofsky, Tien Peng
Abstract
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.
Datasets
1. immune cells
Metadata
donor_id
seurat_clusters
celltype
organism_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
tissue_ontology_term_id
sex_ontology_term_id
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cell_type_ontology_term_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
ALveolar Macrophage680 cells NCBITaxon:960635699 cells UBERON:000229935699 cells HsapDv:000015711720 cells natural killer cell3709 cells alveolar macrophage680 cells pulmonary emphysema22789 cells alveolus of lung35699 cells 63-year-old human stage11720 cells 65-year-old human stage7646 cells 73-year-old human stage7592 cells 61-year-old human stage5817 cells 60-year-old human stage2924 cells 2. non-immune cells
Metadata
donor_id
seurat_clusters
celltype
organism_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
tissue_ontology_term_id
sex_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
cell_type_ontology_term_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
Distal fibroblast2826 cells Proximal fibroblast2076 cells Peribronchial fibroblast513 cells NCBITaxon:960618386 cells UBERON:000229918386 cells endothelial cell5874 cells type II pneumocyte2891 cells smooth muscle cell1652 cells endothelial cell of lymphatic vessel730 cells epithelial cell of lower respiratory tract710 cells type I pneumocyte673 cells pulmonary emphysema9003 cells alveolus of lung18386 cells 63-year-old human stage6182 cells 65-year-old human stage3651 cells 73-year-old human stage3635 cells 60-year-old human stage3262 cells 61-year-old human stage1656 cells 3. AT2 cells
Metadata
donor_id
seurat_clusters
celltype
organism_ontology_term_id
assay_ontology_term_id
self_reported_ethnicity_ontology_term_id
tissue_ontology_term_id
sex_ontology_term_id
development_stage_ontology_term_id
disease_ontology_term_id
cell_type_ontology_term_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
type II pneumocyte3662 cells pulmonary emphysema1219 cells alveolus of lung3662 cells 63-year-old human stage1262 cells 61-year-old human stage839 cells 60-year-old human stage590 cells 73-year-old human stage525 cells 65-year-old human stage446 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/03cdc7f4-bd08-49d0-a395-4487c0e5a168
Alias names
Emphysema Cell Atlas, GSE196638, PMC10578134, PMID36822205
Cite this study
Wang, C., Hyams, B., Allen, N.C., Cautivo, K., Monahan, K., Zhou, M., Dahlgren, M.W., Lizama, C.O., Matthay, M., Wolters, P. and Molofsky, A.B., 2023. Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir. Immunity, 56(3), pp.576-591. https://doi.org/10.1016/j.immuni.2023.01.032
