J. Ruwisch, H. Yilmaz, L. Christian, L. Neubert, L. M. Leiber, A. Brueggemann, S. Banerjee, M. Greer, W. Rackwitz, L. Giercke, C. Werlein, C. A. Pawlow, R. Engelhardt, A. Coppens, M. Ballmaier, E. Chichelnitskiy, S. Simon, J. Salman, K. Aburahma, A. O. Yildirim, J. Gote-Schniering, J. Hohlfeld, B. Vanaudenaerde, D. D. Jonigk, S. Dettmer, F. Ius, M. M. Hoeper, S. Gaedcke, N. Kaminski, Y. Li, S. E. Verleden, J. Gottlieb, C. Falk, J. C. Kamp, J. C. Schupp
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 structural cell states populate the BOS graft and how they are spatially organized during airway obliteration. Methods: We profiled explanted lungs from 33 BOS patients undergoing re-transplantation and 33 controls, combining single-nucleus RNA sequencing (14 BOS, 13 controls) with targeted spatial transcriptomics of 108 regions (27 BOS, 24 controls) and multiplex immunofluorescence validation. Single-nucleus data were integrated with a published restrictive allograft syndrome (RAS) atlas. Results: Across 175,128 nuclei and 1.67 million spatially resolved cells, BOS lungs harbored a profibrotic circuit of Aberrant Basaloid cells and CTHRC1+ fibrotic fibroblasts previously described in fibrotic lung diseases, including RAS. Spatial mapping identified a CXCL14+TNC+ injury-associated basal cell state arising early in the obliterative cascade, identifying basal cells as their major reservoir. CTHRC1+ fibroblasts expanded subepithelially replacing resident peribronchial fibroblasts, alongside a peribronchial vascular shift toward systemic venous endothelium. The circuit extended beyond the airway wall to the alveolar interface, defining two convergent remodeling fronts. Conclusion: BOS engages structural-cell circuits largely shared with RAS and fibrotic lung diseases, but along an airway-centered rather than parenchyma-centered axis. CLAD thus emerges as a spatial rather than cellular spectrum, defined by anatomical distribution more than cell identity. Shared structural programs may therefore be targetable across CLAD phenotypes.