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Aberrant and Ectopic Cell Populations in Restrictive Allograft Syndrome after Lung Transplantation
Lena M Leiber1,2, Leonard Christian1,2, Lavinia Neubert2,3
1Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany.
Rationale:
Restrictive allograft syndrome (RAS) is a major cause of mortality following lung transplantation due to progressive fibrosis of the lung allograft with no therapeutic options. Knowledge of the cellular and molecular mechanisms driving fibrosis in RAS remains limited.
Objective:
To characterize the cellular and molecular changes in human RAS lungs through single-cell transcriptomic profiling.
Methods:
Single-nucleus RNA-sequencing (snRNA-seq) was performed in peripheral lung tissues from 15 RAS patients undergoing lung re-transplantation, and from 9 healthy control lungs. Findings were validated and extended using histologic techniques including immunofluorescence, RNA in situ hybridization, Elastica-van-Gieson immunohistochemistry, quantitative histological analyses, and micro-CT scans.
Measurements And Main Results:
snRNA-seq analysis of RAS lungs revealed previously undescribed aberrant basaloid cells, ectopic COL15A1+ peribronchial vascular endothelial cells (pVECs), and CTHRC1+ fibrotic fibroblasts. Histologic stains disclosed distinctive distribution patterns: aberrant basaloid cells, primarily localized at the fibrotic edge, together with juxtaposed CTHRC1+ fibrotic fibroblasts and ectopic COL15A1+ pVECs form the fibrotic niche of alveolar fibroelastosis (AFE). PRX+ alveolar microvasculature is partially lost in AFE areas. Micro-CT scans revealed changes from pulmonary to systemic perfusion, facilitated by COL15A1+ pVECs. Last, our data reveals potential therapeutic targets in RAS, including integrin αvβ6, activator of TGFβ.
Conclusion:
Considering the multifaceted differences of RAS and idiopathic pulmonary fibrosis, we revealed a surprising general principle of an entity-spanning composition of the fibrotic niche by aberrant basaloid cells localized at the fibrotic edge, ectopic COL15A1+ pVECs and CTHRC1+ fibrotic fibroblasts. This suggests a flexible but cellular pathogenesis-guided transferability of potential therapeutic approaches between progressive fibrotic lung diseases.
Insights
Restrictive allograft syndrome (RAS) involves unique fibrotic lung niches with aberrant basaloid cells and vascular changes. This study identifies potential therapeutic targets for lung transplantation fibrosis.
Area of Science:
- Pulmonary Medicine
- Transplantation Immunology
- Fibrotic Lung Diseases
Background:
- Restrictive allograft syndrome (RAS) is a leading cause of lung transplant mortality due to progressive allograft fibrosis.
- Current understanding of the cellular and molecular drivers of RAS fibrosis is limited, hindering therapeutic development.
Purpose of the Study:
- To comprehensively characterize the cellular and molecular landscape of human RAS lungs.
- To identify novel cellular populations and molecular pathways involved in RAS pathogenesis using single-cell transcriptomics.
Main Methods:
- Single-nucleus RNA-sequencing (snRNA-seq) was performed on peripheral lung tissues from RAS patients and healthy controls.
- Histologic techniques including immunofluorescence, RNA in situ hybridization, and micro-CT scans were used for validation and spatial characterization.
Main Results:
- snRNA-seq identified aberrant basaloid cells, ectopic COL15A1+ peribronchial vascular endothelial cells (pVECs), and CTHRC1+ fibrotic fibroblasts in RAS lungs.
- These cells form a distinct fibrotic niche associated with alveolar fibroelastosis (AFE), loss of microvasculature, and altered perfusion.
- Potential therapeutic targets, including integrin αvβ6 and TGFβ activator, were identified.
Conclusions:
- RAS pathogenesis involves a unique fibrotic niche composed of aberrant basaloid cells, ectopic pVECs, and fibrotic fibroblasts.
- This finding suggests shared pathogenetic principles across progressive fibrotic lung diseases, enabling transferable therapeutic strategies.
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