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Single-cell RNA-seq of bronchoalveolar lavage from bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

ABSTRACT: Chronic lung graft-versus-host disease (GVHD) and bronchiolitis obliterans syndrome (BOS) are major causes of late non-relapse morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To dissect airway immune–epithelial remodeling and nicotinamide adenine dinucleotide (NAD⁺) metabolic imbalance in this setting, we performed single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) obtained from BOS lesions and matched non-lesion airways in allo-HSCT recipients. Using 10x Genomics Single Cell 3′ chemistry, we generated an integrated atlas of airway epithelial, myeloid, and lymphoid populations and quantified changes in cellular composition, macrophage polarization, and NAD⁺-axis gene programs between BOS and control regions. This dataset provides a human airway single-cell resource for studying chronic lung GVHD, immune–epithelial crosstalk, and metabolism-centered therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313529 | GEO | 2026/09/09

REPOSITORIES: GEO

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Project description:Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality in allogeneic-hematopoietic stem cell transplantation with bronchiolitis obliterans syndrome (BOS) among the most lethal treatment-resistant complications. Despite approval of 4 second-line therapies, clinical response in moderate and severe BOS patients remains poor. Bromodomain and Extra terminal (BET) proteins are epigenetic readers driving oncogenic and inflammatory transcriptional programs in multiple cell types. We hypothesized that BET inhibition would be a feasible therapeutic option by restraining the direct inflammatory T cells as well as macrophage polarization to profibrotic phenotype known. We used an established BOS cGVHD model wherein we treated cGVHD mice with the translatable BET inhibitor: OPN-51107 (BETi). We found that under BETi, T and B cells had reduced germinal center (GC) trafficking ability, and GC activation resulting in reduced IgG1+ class switched B cells. Mice with cGVHD had elevated pathogenic IgM and IgG1 both in circulation and deposited onto lung tissue, which was attenuated under BET inhibition. Furthermore, antibodies produced in cGVHD were both allo- and auto-reactive. Single-cell RNA sequencing analysis revealed 22 distinct cell types in the BOS lung. In cGVHD mice, GSEA analysis revealed upregulation of anti-inflammatory Arginase1 and profibrotic Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced in BETi treated mice. Spectral flow cytometry confirmed that BETi targeted lung-infiltrating M2 macs, through diminishment of CD206+FcgR+ M2 IMs and AMs. Ultimately, this concluded in reduced collagen deposition and improved lung function in mice treated with BETi. We identify BET proteins as a key regulator of inflammation in BOS. BETi suppresses Tfh and GC B cells, thereby reducing Ab production and deposition. Within the lung, BETi selectively targets M2 IM macs to reduce FcgR and TGF-b expression, thereby regulating collagen deposition and fibrosis. These findings reveal a previously unrecognized mechanistic axis driving cGVHD and highlight BET inhibition as a promising therapeutic strategy.

Project description:Background: Mesenchymal stromal cells (MSC) have been proposed as a future cell based therapy for lung diseases like bronchiolitis obliterans syndrome (BOS). Theoretically, it might be beneficial to use lung resident MSC already adapted to the pulmonary environment. We therefore aimed to compare lung MSC with the well-characterized bone marrow MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to MSC isolated from good outcome recipients. Methods: MSC were isolated from bone marrow (BM) and adult/fetal lung tissues and compared by a comprehensive panel of assays. Results:The gene expression profiles of adult lung derived and fetal lung derived MSC were very similar compared to BM derived MSC, with only 235 and 338 genes, respectively, being significantly differently expressed. Out of the 235 genes that were significantly different between adult lung derived and BM derived MSC, 90 genes were higher expressed in the lung derived MSC. In case of fetal lung derived MSC, 166 genes were higher expressed compared to the BM derived MSC. Interestingly, only, 89 genes were found to be expressed differently when comparing BM derived MSC to both, fetal and adult lung derived MSC, indicating that these genes are lung specific. Next, we went on to evaluate if MSC isolated from biopsies of lung-transplanted patients with BOS differed compared to patients without BOS, i.e. good outcome recipients. Here we found that four genes (Sox9, FAR2, LOC728855 and NDUFS5) were significantly higher expressed in MSC isolated from BOS patients Conclusions: This data demonstrates that lung resident MSC possess lung specific properties that should be taken into considerations when using MSC for cell-based therapy in severe lung disorders like BOS. These results also show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype. Comparison of gene expression of MSC isolated from bone marrow, adult lung and fetal lung.

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Single-cell RNA-seq of bronchoalveolar lavage from bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

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