Single-cell and spatial transcriptomics resolve airway obliteration in bronchiolitis obliterans syndrome
Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation, and its most frequent phenotype is bronchiolitis obliterans syndrome (BOS), a fibrotic small-airway disease. Mechanistic work has focused on the immune compartment, yet intensified immunosuppression does not alter established disease. Aim: To resolve which…
The study aimed to understand the structural cell states involved in bronchiolitis obliterans syndrome (BOS), a fibrotic small-airway disease associated with chronic lung allograft dysfunction (CLAD). Researchers analyzed explanted lungs from BOS patients undergoing re-transplantation and controls using single-nucleus RNA sequencing and targeted spatial transcriptomics. Both techniques were integrated with a published restrictive allograft syndrome (RAS) atlas.
The results revealed that BOS lungs contained a profibrotic circuit of Aberrant Basaloid cells and CTHRC1+ fibrotic fibroblasts. Spatial mapping showed that these cells formed two convergent remodeling fronts, extending beyond the airway wall to the alveolar interface. The circuit began with a CXCL14+TNC+ injury-associated basal cell state, which served as the major reservoir of these cells.
CTHRC1+ fibroblasts expanded subepithelially, replacing resident peribronchial fibroblasts and causing a vascular shift towards systemic venous endothelium.
The findings suggest that BOS engages structural-cell circuits similar to those in RAS and other fibrotic lung diseases, but the disease develops along an airway-centered axis rather than a parenchyma-centered one. This implies that CLAD is a spatial rather than cellular spectrum, defined more by anatomical distribution than cell identity. The shared structural programs identified in this study may be targetable across various CLAD phenotypes.
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