Jun‐Wei B. Hughes, Akshay Pujari, Anja Sandholm, Duncan Croll, Lea B. Monk, Isaac Joshua, Rachel Butterfield, Corrigan Horton, Kevin Schneider, Fiona Senchyna, Ian R. Brown, Zhixin A. Zhang, T. Ho, Tsung-Che Ho, Hideto Deguchi, Ryo Higuchi-Sanabria, Claude Jourdan Le Saux, Stefanie Deinhardt‐Emmer, Lisa Ellerby, Alberto Vitari, David Furman, Cory M. Hogaboam, Alex Laslavic, Pierre‐Yves Desprez, Marco Quarta, Judith Campisi
Cellular senescence is a highly heterogeneous state of cell stress response that deleteriously accumulates with age and contributes to age-related dysfunction. While the heterogeneity across cell types is well documented, variation within the same cell type is only beginning to be understood. Here, we show primary human lung fibroblasts from either donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair and cytokine and chemokine responses. We combine our healthy and IPF senescent gene expression datasets to develop a novel gene signature of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine, and chemokine targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.