Biology subjects

Hughes, J.-W. B.

Publications and source records attributed to Hughes, J.-W. B..

3 recordsLinked to original sources

bioRxiv2026

Cellular senescence dysregulates antiviral interferon responses in idiopathic pulmonary fibrosis

Patients with idiopathic pulmonary fibrosis (IPF) are highly vulnerable to respiratory virus infections, but the cellular mechanisms linking fibrotic remodeling to impaired local antiviral defense remain unclear. Here, we investigated how cellular senescence shapes the response of patient-derived healthy and IPF primary lung fibroblasts to influenza A virus (IAV) infection. Transcriptomic profiling identified infection as the driver of gene expression in both DNA damage-induced senescent healthy and IPF fibroblasts and revealed induction of canonical antiviral pathways in both cell states. However, senescent IPF fibroblasts adopted a distinct antiviral response state characterized by a broader set of uniquely induced genes and differential coordination of antiviral transcriptional networks. Functionally, senescence increased viral titers in healthy and IPF fibroblasts, while senescent IPF fibroblasts displayed an altered inflammatory response. Network analysis linked viral response- and cell cycle-associated modules specifically to the senescent healthy infected state, whereas these programs were weaker in senescent IPF fibroblasts. Transcription factor inference identified IRF3 and STAT1 as candidate regulators of this altered antiviral state in both senescent healthy and IPF fibroblasts. Consistent with the network and transcription factor analyses, siRNA-mediated depletion of IRF3 or STAT1 significantly reduced IFN-{beta} secretion in senescent healthy fibroblasts, whereas IPF fibroblasts showed only milder effects, indicating a disease-specific dependence on these pathways for antiviral control. Together, these findings show that the combination of cellular senescence and fibrotic fibroblast identity creates a dysfunctional antiviral state that may help explain the high susceptibility of IPF patients to virus-associated acute exacerbations and disease worsening.

cell biology↗

bioRxiv2026

DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons

Alzheimers disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.

cell biology↗

bioRxiv2025

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

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.

cell biology↗