Small airway fibroblasts from COPD patients are senescent and pro-fibrotic

Wrench, Catherine; Baker, Jonathan; Fenwick, Peter; Donnelly, Louise; Barnes, Peter J.

doi:10.1183/13993003.congress-2018.pa2172

Cited by 5 publications

(6 citation statements)

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“…Similarly, phLF obtained from IPF lung tissue, showed decreased proliferation rates, increased expression of CDKN1A/P21, CDKN2A/P16, and TP53 as well as senescence-related morphological changes (16). The fact that we did not observe any major differences in senescence markers among disease origin, as reported previously (16,30,32,33), could be explained by different isolation protocols. For example, in this study we isolated phLF by enzymatic digestion contrary to outgrowth from tissue pieces that other studies used (32).…”

Section: Discussionsupporting

confidence: 78%

“…However, all these markers increased with prolonged culture as described for replication-induced senescence (31). Previous studies showed that fibroblasts originated from COPD patients had an elevated senescence signature as judged by enhanced expression of P21/CDKN1A and CDKN2A/P16, increased SA-β-galactosidase activity (32,33), reduced proliferation rates (30,33) and higher secreted levels of proteins associated with the SASP (15). Moreover, they inhibited canonical WNT-βcatenin signaling in alveolar epithelial cells by secreting WNT-5A, leading to stem cell exhaustion and impaired lung repair (34).…”

Section: Discussionmentioning

confidence: 95%

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Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function

Bramey,

Melo-Narvaez,

See

et al. 2023

Preprint

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Aging is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are increased in different cell types such as fibroblasts in the lungs of these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H2O2and bleomycin treatment induced a senescent phenotype in phLF whereas TGF-β1 only had a pro-fibrotic effect. Interestingly, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin. However, exposure to different stimuli resulted in different senescent programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of alveolar epithelial progenitor cells. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacityin vitro.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 95%

Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function

Bramey,

Melo-Narvaez,

See

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, intrinsic characteristics like the smoking history or passage number, as well as different culturing conditions and media supplementation can in uence senescence readouts [40]. Finally, the composition of the isolated phLF can also vary depending on different anatomical localizations such as airway [38,41] versus whole lung [16,35] and current isolation methods do not discriminate among the different broblast subtypes recently described for the lung. In the past decades, it was believed that ACTA2 + positive myo broblasts were the main contributor for ECM deposition in the IPF lung [19].…”

Section: Discussionmentioning

confidence: 99%

Stimuli-specific senescence of primary human lung fibroblasts modulates alveolar stem cell function

Bramey,

Melo-Narvaez,

See

et al. 2024

Preprint

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Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are present in different lung cell types such as fibroblasts in these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD patients differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H2O2 and bleomycin treatment induced a senescent phenotype in phLF, whereas TGF-β1 had primarily a pro-fibrotic effect. Notably, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin, while exposure to different stimuli resulted in distinct senescence programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of distal alveolar epithelial progenitor cells in a stimuli-dependent manner. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacity in vitro.

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“…Due to these opposing fibroblast mediated pathologies in the COPD airway and parenchyma, it has been considered for some time that different populations of fibroblast contribute to the two different features of COPD, however only limited profiling has been performed. Small airway fibroblasts in COPD are profibrotic (secrete collagens 1A1/3A1, MMP2 and MMP9), pro-inflammatory (increased CXCL8 secretion), senescent (elevated p21 and p16 expression) [70] and express reduced levels of antioxidants (Superoxide dismutase 2 and 3) [73,74]. Parenchymal fibroblasts in COPD display reduced proliferation [75], reduced capability to sustain tissue repair (increased PGE2 production and EP2/EP4 expression, reduced response to TGFβ) [76], reduced contractility [76,77], reduced migration to chemoattractants [76] and increased expression and secretion of CXCL8 and IL-6 [78].…”

Section: Chronic Obstructive Pulmonary Disease (Copd)mentioning

confidence: 99%

DNA Methylation of Fibroblast Phenotypes and Contributions to Lung Fibrosis

Rajasekar

Patel

Clifford

2021

Cells

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Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions including the secretion of bioactive molecules and antigen presentation. DNA methylation is the covalent attachment of a methyl group to primarily cytosines within DNA. DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence, with DNA methylation profiles providing a memory of cellular origin. The lung fibroblast population is increasingly viewed as heterogeneous with between 6 and 11 mesenchymal populations identified across health and lung disease to date. DNA methylation has been associated with different lung fibroblast populations in health and with alterations in lung disease, but to varying extents. In this review, we will discuss lung fibroblast heterogeneity and the evidence for a contribution from DNA methylation to defining cell populations and alterations in disease.

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Small airway fibroblasts from COPD patients are senescent and pro-fibrotic

Cited by 5 publications

References 0 publications

Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function

Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function

Stimuli-specific senescence of primary human lung fibroblasts modulates alveolar stem cell function

DNA Methylation of Fibroblast Phenotypes and Contributions to Lung Fibrosis

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