Single-cell transcriptomic analysis of the heterogeneity of mesenchymal and stromal cells and their regulon alteration during airway remodeling in asthma

Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach for immune-mediated diseases, including asthma, which is characterized by persistent airway inflammation and remodeling. Accumulating research evidence highlights the critical involvement of cellular heterogeneity in disease pathogenesis. In this study, we explored the heterogeneity of mesenchymal and stromal cell populations and their contribution to asthma pathogenesis by comprehensively analyzing single cell transcriptomic data from a cynomolgus monkey model of asthma. We have identified 10 stromal and 4 mesenchymal subpopulations, each with distinct functions and divergent responses to airway inflammation and remodeling. Under the disease state, regulons of FOXF1, ETS1, ETS2, GATA3 and RELB were significantly activated, while those of MECOM, SOX17, LTF, FOS and PBX1 were repressed in an important stromal subpopulation (endothelial cells); regulons of NR3C1 and DBP were significantly activated in the mesenchymal subpopulation MC0. Strikingly, the cell-cell communications involving two mesenchymal subpopulation MC1 and MC3 were completely lost during asthma pathogenesis, while those involving MC0 and MC2 were primarily upregulated. We also applied bulk RNA-seq analysis to validate the regulon results, revealing a consistent decrease in the PPARG expression, which has be further validated using a mouse asthma model established in this study. These findings underscore the importance of heterogeneity of mesenchymal and stromal cells in mediating the airway inflammation and remodeling, suggesting that the active and suppressive regulons may represent novel targets for asthma therapeutics.