Abstract
Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology.
Highlights
In comparison with Idiopathic pulmonary fibrosis (IPF)-noTRG patients, IPF-telomere related genes (TRGs) patients tended to be more frequently referred to lung transplantation rather than to surgical lung biopsy (6/7 vs. 2/6, p = 0.10)
The analysis revealed a significant reduction in telomere signal intensity in lung fibroblasts from both categories of IPF patients compared to those in controls (p = 2.2 × 10−16, Wilcoxon–Mann–Whitney), and from IPF-noTRG lung fibroblasts compared to IPF-TRG lung fibroblasts (p = 2.2 × 10−16, Wilcoxon–Mann–Whitney)
We confirm that lung-derived fibroblasts from IPF patients exhibit shorter telomere confirm that lung-derived fibroblasts from IPF patients exhibit shorter telomere length, as length, as assessed by their lower telomere fluorescence intensity than cells from control assessed by their lower telomere fluorescence intensity than cells from control fibroblasts, fibroblasts, andfor we show the first time that telomere lengths are more heterogeneous and we show the first for time that telomere lengths are more heterogeneous in IPF fibrobin fibroblasts than in controls
Summary
The fundamental role of telomeres is creativecommons.org/licenses/by/ 4.0/). Biomedicines 2022, 10, 310 to preserve genome stability [1,2]. Loss of telomere functionality is associated with activation of DNA damage response machinery that can result in chromosome end-to-end fusions and instability [3–5]. Human genetic defects that impair telomere length maintenance cause premature age-related diseases, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, and idiopathic pulmonary fibrosis (IPF) [6,7]. Germline mutations in telomere related genes (TRG), such as TERT, RTEL1, TERC or PARN, are detected in approximately 30% of patients with familial pulmonary fibrosis [9–13]. This observation ascertains for a causal link between impaired telomere length maintenance and predisposition to develop pulmonary fibrosis.
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