Bronchiolitis obliterans syndrome (BOS) is an alloimmune complication with complex pathophysiology, arising after hematopoietic stem cell transplantation (HSCT) or lung transplantation (LT), leading to high morbidity and mortality. This study investigates how transplantation impacts the integrity and regenerative capacity of the respiratory epithelium, as factors such as compromised mucosal integrity or immune dysregulation, may contribute to BOS. Although HSCT and LT involve distinct transplantation contexts, both can lead to BOS. By comparing HSCT, LT, and control epithelia, we aimed to identify common factors predisposing to BOS and increase the relevance of our findings.

We developed an ex vivo model of human airway epithelia (HAE) using bronchial biopsies from HSCT, LT, and non-transplanted control patients. The HAE model was assessed through phenotypic characterization. Additionally, airway epithelial chimerism was evaluated in transplant recipients. Single-cell RNA sequencing provided transcriptional profiles for each HAE.

We developed an ex vivo HAE model that accurately replicates epithelial phenotypes from HSCT, LT, and control patients. Our findings showed that transplantation procedures distinctly affect the respiratory epithelium. Specifically, we demonstrated that HSCT-derived HAE exhibited impaired differentiation compared to LT-derived HAE, and that HSCT conditioning regimen detrimentally affected epithelial differentiation. Upon infection with human parainfluenza virus 3 and SARS-CoV-2, we observed differential susceptibility between transplanted and control HAE.

In summary, this study established an ex vivo HAE model that faithfully reflects the phenotypic and functional characteristics of respiratory epithelia from LT, HSCT, and control patients. Our results underscore the distinct effects of transplantation regimens on epithelial differentiation and antiviral responses, highlighting potential mechanisms contributing to BOS development in transplant recipients.