Characterizing the B-cell senescence signature in driving the disease phenotype in COPD/emphysema

Characterizing the B-cell senescence signature in driving the disease phenotype in COPD/emphysema. Download PDF Abstract Background Increased cellular senescence is a key mechanism underlying chronic inflammation and airway remodeling in chronic obstructive pulmonary disease (COPD). Yet, the cellular composition and molecular features of the senescent microenvironment in COPD remain poorly understood.

Methods To address this gap, we employed a multi-omics approach to identify senescence-associated differentially regulated cell populations and associated genes in smoke-induced emphysema. Single-cell RNA sequencing analyses of 121,885 lung cells from COPD patients and healthy controls ( n = 6 per group), including individuals with (Sm) and without (NS) a smoking history, were analyzed using standard approaches. Results Our analyses reveal a significant enrichment (p < 0.05) of senescence-associated gene signatures within B-cell clusters from COPD lungs.

The transcriptional profile of senescent B cells include: (a) impairment of B cell differentiation and maturation ( KITLG, PRDM1), (b) increase in inflammatory signaling ( CXCL3, IL6, GDF15), and (c) dysregulation of lipid metabolism ( PTGS2), thereby releasing factors affecting ECM composition ( MMP14) and cell-cell interactions in COPD. Spatial transcriptomics and proteomics validate the scRNA seq findings. We identify distinct ‘senescent’ niches within COPD lungs that shows persistent inflammatory signaling, activation of p16-mediated senescence, and dysregulation of intercellular communication.

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