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Transcriptomic profiling of murine liver, lung, and adipose functional cells across aging and chronic disease models [RNA-Seq]

ABSTRACT: To identify organ-specific SASP factors associated with mesenchymal drift in liver, lung, and adipose diseases, we performed RNA‑seq on primary hepatocytes (mPHs) from STAM mice, pulmonary fibroblasts (mPLFs) from bleomycin‑induced IPF mice, and adipose‑derived MSCs (mADSCs) from obese mice, as well as from normal and naturally aged mice. Compared with controls, the upregulated genes shared across each disease model and aged mice were defined as mesenchymal drift‑associated SASP (MD‑SASP) signatures. We identified 10 hepatic, 8 pulmonary, and 8 adipose MD‑SASP factors, including liver‑specific Il‑8/Tgfb3/Edn1/Cxcl16, lung‑specific Il6/Igfbp7, and adipose‑specific Fgf7/Timp1. These factors can serve as candidate indicators for evaluating cellular interstitial senescence in future studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE342841 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Cellular senescence and the senescence-associated secretory phenotype (SASP) broadly contribute to age-related endothelial dysfunction, in part, by promoting oxidative stress (a key source being mitochondria) and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we leveraged aortic single-cell transcriptomics to characterize specific vascular senescent cells and SASP profiles in young (6mo) vs. old (27mo) mice. In vivo supplementation with the natural senolytic compound fisetin allowed for the assessment of senescent cell signatures with aging and senolytic intervention. Both aging and senolytic treatment had the greatest effect on endothelial cell populations. As such, we focused on senescent-specific molecular changes in endothelial cells. Senescent endothelial cells demonstrated increased abundance of transcripts related to cardiovascular pathology and high expression of SASP factors. Of the identified SASP factors that had higher expression with aging, Cxcl12 mRNA was the most highly upregulated with old age and downregulated with senolytic treatment and this pattern persisted in circulating CXCL12 protein concentrations in plasma. We next sought to determine the causal role of the circulating SASP milieu and CXCL12 in regulating endothelial function with aging and fisetin supplementation. Ex vivo exposure of isolated arteries and cultured endothelial cells to plasma from young, old and old fisetin-supplemented mice revealed that the aged circulating SASP milieu directly induced endothelial dysfunction through induction of cellular senescence induction, reduced NO bioactivity, and increased mitochondrial oxidative stress. The circulating SASP milieu-mediated impairments were in part mediated by CXCL12 and subsequently alleviated by fisetin supplementation. These findings establish the circulating SASP milieu as an underlying mechanism of age-related endothelial dysfunction and identify CXCL12 as a novel mediator and therapeutic target of cellular senescence-induced endothelial dysfunction with aging.

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Transcriptomic profiling of murine liver, lung, and adipose functional cells across aging and chronic disease models [RNA-Seq]

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