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Profiling of cultured primary stromal cells from human lung

ABSTRACT: Recent publications have implicated senescent alveolar epithelial cells as the cause of lung remodeling and fibrosis. We sought to better understand the heterogeneity in the basal epithelial cell population, especially with regards to characterizing senescent alveolar epithelial cells. The basal cell cultures contain a portion of cells that display a senescent phenotype and stain for a marker of senescence. We also sought to understanding the heterogeneity in the fibroblast population. Primary fibroblast cultures stained with myofibroblast markers show that only a portion of the cells are positive for ACTA2, suggesting that there are at least two distinct populations in this particular cell type. The diversity in this cell type remains uncharacterized at this point.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166037 | GEO | 2021/03/08

REPOSITORIES: GEO

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Project description:Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modelled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-Seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted species-specific responses to telomere dysfunction. We then conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.

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Profiling of cultured primary stromal cells from human lung

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