Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis

Dec 15, 2025bioRxiv : the preprint server for biology

Different types of aging fibroblast cells link DNA damage to unexplained lung fibrosis

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Abstract

Primary human lung fibroblasts from healthy donors and those with idiopathic pulmonary fibrosis exhibit a subtle form of heterogeneity after DNA damage.

Cellular senescence shows variability even within the same cell type, highlighting the complexity of this state.
Senescent lung fibroblasts from patients with idiopathic pulmonary fibrosis display an abnormal response to DNA damage.
Analysis of gene expression reveals relationships between senescent cell heterogeneity and genes linked to DNA damage, inflammation, and tissue structure.
A new set of senescence-associated genes was identified, which may help locate disease-relevant cells in single-cell gene expression data.

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Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from 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, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set 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, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.

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Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis

Abstract

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