Spatial Transcriptomics in COPD: Insights into Smoking-Induced Pathophysiological Changes
- Publication Type:
- Thesis
- Issue Date:
- 2025
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The spatial architecture of the lung is essential for maintaining homeostasis, enabling efficient gas exchange, and mounting immune responses to external respiratory challenges such as infections and pollutants. Chronic obstructive pulmonary disease (COPD) is a complex, progressive, and heterogeneous lung disease characterised by chronic inflammation, airway remodelling, and alveolar destruction (emphysema), leading to irreversible airflow limitation and breathing difficulties. COPD is the third leading cause of death globally, with cigarette smoking as the predominant risk factor. Current therapies alleviate symptoms but fail to halt disease progression, reflecting an incomplete understanding of disease mechanisms. Although single-cell transcriptomics has advanced our molecular understanding of COPD, its spatial context remains largely unexplored.
Chapters 2 and 3 of this thesis examine the cellular and molecular dynamics across lung regions, revealing new insights into COPD pathogenesis. Using experimental mouse models of chronic cigarette smoke exposure, we applied spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) to map cell-type-specific gene expression within the lung microenvironment. These studies identified alveolar macrophages migrating from pulmonary vasculature to distal parenchyma and the progressive enlargement of lymphoid follicles with ongoing smoke exposure. The distal parenchyma and lymphoid follicles emerged as previously underexplored sites of pathogenesis, offering new perspectives on disease progression.
Chapter 4 investigated the epigenetic effects of cigarette smoking on human airways. A distinct “smoking signature” gene set was identified that robustly distinguished current smokers from non-smokers. Spatial and single-cell analyses revealed smoke-induced injury concentrated in the airway surface epithelium. Comparative studies between human and non-human primate lungs identified a “human lung evolution signature,” suggesting evolutionary adaptation to chronic smoke exposure. Transcription factors NRF2 and AhR were found to regulate this response via target genes NQO1 and ALDH3A1, whose knockout studies confirmed protective roles against smoke toxicity.
Chapter 5 examined cellular senescence in COPD, demonstrating that senescent cells accumulate and contribute to pathology. Senolytic treatment eliminated these cells, reduced immune infiltration, and partially improved lung structure, though functional recovery was limited. These findings suggest senolytics may serve as a complementary therapy for COPD.
Overall, this thesis integrates spatial and molecular insights to advance the understanding of COPD pathogenesis. By bridging experimental models and human studies, it provides a framework for developing precision medicine strategies to better manage and treat COPD.
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