Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis
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Résumé
Abstract Rationale The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
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La notice
- Revue
- American Journal of Respiratory and Critical Care Medicine
- Thématique
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Domaine
- Medicine
- Établissements canadiens
- —
- Organismes subventionnaires
- National Institute of Environmental Health SciencesNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of Allergy and Infectious DiseasesNational Institute on AgingNational Institutes of HealthUnited States-Israel Binational Science FoundationNational Cancer InstituteNational Research FoundationNorthwestern Memorial FoundationScleroderma FoundationRheumatology Research FoundationRespiratory Health AssociationNational Heart, Lung, and Blood InstituteNorthwestern UniversityNational Center for Advancing Translational SciencesMallinckrodt PharmaceuticalsU.S. Department of DefenseAmerican Lung AssociationArthritis National Research FoundationU.S. Department of Veterans Affairs
- Mots-clés
- Pulmonary fibrosisLungMedicineIdiopathic pulmonary fibrosisFibrosisCellPathologySingle-cell analysisWnt signaling pathwayCell typeTranscriptomeImmunologyBiologyGene expressionGeneInternal medicineGenetics
- Résumé présent dans OpenAlex
- oui