Investigating the role of aging and lung fibrosis in Endothelial Cells with RNA sequencing
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE181508 | GEO | 2021/09/30
REPOSITORIES: GEO
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Project description:In order to elucidate the contribute of the pulmonary vasculature to lung fibrosis, we injured young and aged mice with bleomycine, to create a model of resolving versus persistent lung fibrosis. The animals were sacrificed 30 days after the injury (time point in which we observed a divergent resolving vs persistent lung fibrosis in young vs aged mice).
2022-05-09 | GSE177055 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by the accumulation of myofibroblasts leading to the progressive scarring of the lung. To identify transcriptional gene programs driving persistent fibrosis in aged lungs, we performed a comparative RNA-seq analysis of fibroblasts freshly isolated from young and aged mouse lungs 30 days post-bleomycin injury. We discovered that lung fibroblasts isolated from young animals at this time point post-injury were transcriptionally similar to those isolated from uninjured mice. In contrast, aged lung fibroblasts isolated at the same time point exhibited a sustained pro-fibrotic state characterized by the elevated expression of genes implicated in inflammation, extracellular matrix remodeling, and cell survival. We identified the protein kinase pro-viral integration site of Moloney murine leukemia virus 1 (PIM1) and its direct target Nuclear Factor of Activated T Cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures observed in aged lung fibroblasts post-injury. PIM1 and NFATc1 transcripts were highly enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was detected in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation and this effect was dependent on NFATc1. Pharmacological inhibition of PIM1 in IPF-derived lung fibroblasts attenuated their activation and sensitized them to apoptotic stimuli. Finally, inhibition of PIM1 strongly reduced the expression of ECM remodeling and pro-survival genes and blocked the secretion of collagen in IPF lung explants ex vivo. Targeting PIM1/NFATc1 axis in pathogenic lung fibroblasts may represent a therapeutic strategy to limit their activation and promote fibrosis resolution in IPF.
2022-01-01 | GSE191208 | GEO
Project description:The capacity of lung tissue to heal without scarring deteriorates with aging. The pulmonary vasculature has emerged as a central regulator of lung repair, and aging-associated endothelial cell dysfunction has been associated with defective lung response to injury and sustained fibrosis. To shed light into aging-associated cellular and transcriptional responses of lung endothelial cells during lung fibrogenesis, we carried out a single cell RNA-seq analysis of bleomycin-treated young (2 months) and aged (72 months) lungs during the early phase of fibrosis resolution (30 days post bleomycin). This analysis revealed that lung injury was associated with the appearance of distinct populations of endothelial cells that exhibit “activated” transcriptional states, originating from virtually all vascular beds. Activated endothelial cells deriving from venous and capillary beds were the most represented in aged compared to young lungs. Longitudinal single-cell analysis together with lineage tracing revealed that activated endothelial cells appeared transiently during the peak of collagen production in young lungs and disappeared during the resolution phase. Conversely, activated endothelial cell states persisted in aged lungs around fibrotic areas, indicating a failure of the aged vascular tissue to return to quiescence. We provide evidence that an axis between YAP and TrkB signaling acts as a node that directs injury-induced capillary endothelial cell activation in vivo and lung capillary morphogenesis ex vivo. Together, these data provide insights into the aging-related dynamics of lung endothelial cells in response to injury.
2024-06-04 | GSE264162 | GEO
Project description:The capacity of lung tissue to heal without scarring deteriorates with aging. The pulmonary vasculature has emerged as a central regulator of lung repair, and aging-associated endothelial cell dysfunction has been associated with defective lung response to injury and sustained fibrosis. To shed light into aging-associated cellular and transcriptional responses of lung endothelial cells during lung fibrogenesis, we carried out a single cell RNA-seq analysis of bleomycin-treated young (2 months) and aged (72 months) lungs during the early phase of fibrosis resolution (30 days post bleomycin). This analysis revealed that lung injury was associated with the appearance of distinct populations of endothelial cells that exhibit “activated” transcriptional states, originating from virtually all vascular beds. Activated endothelial cells deriving from venous and capillary beds were the most represented in aged compared to young lungs. Longitudinal single-cell analysis together with lineage tracing revealed that activated endothelial cells appeared transiently during the peak of collagen production in young lungs and disappeared during the resolution phase. Conversely, activated endothelial cell states persisted in aged lungs around fibrotic areas, indicating a failure of the aged vascular tissue to return to quiescence. We provide evidence that an axis between YAP and TrkB signaling acts as a node that directs injury-induced capillary endothelial cell activation in vivo and lung capillary morphogenesis ex vivo. Together, these data provide insights into the aging-related dynamics of lung endothelial cells in response to injury.
2024-06-04 | GSE264151 | GEO
Project description:Idiopathic pulmonary fibrosis is a devastating aging-associated disease of unknown etiology. Despite that aging is a major risk factor, the mechanisms linking aging with this disease are uncertain, and experimental models to explore them in lung fibrosis are scanty. We examined the fibrotic response to bleomycin-induced lung injury in Zmpste24-deficient mice, which exhibit nuclear lamina defects developing accelerated aging. We found that young WT and Zmpste24(-/-) mice developed a similar fibrotic response to bleomycin. Unexpectedly, while old WT mice developed severe lung fibrosis, accelerated aged Zmpste24-/- mice were protected showing scant lung damage. To investigate possible mechanisms associated with this resistance to fibrosis, we compared the transcriptome signature of the lungs and found that Zmpste24(-/-) mice showed downregulation of several core and associated matrisome genes compared with WT mice. Interestingly, some microRNAs that target extracellular matrix molecules such as miR23a, miR27a, miR29a, miR29b-1,miR145a, and miR491 were dysregulated resulting in downregulation of profibrotic pathways such as TGF-β/SMAD3/NF-κB and Wnt3a/β-catenin signaling axis. These results indicate that the absence of Zmpste24 in aging mice results in impaired lung fibrotic response after injury, which is likely associated to the dysregulation of fibrosis-related miRNAs. Aging is a driving force of pulmonary fibrosis. Mice laking Zmpste24 have an accelerated aging phenotype. During the development of the disease there are several extracellular matrix genes, principally collagens upregulated. We use microarray to unveil changes associated with the pulmonary response in aged mice
2018-12-04 | GSE123293 | GEO
Project description:The intent of the experiment is to study the reactivity of human primary blood monocytes during a physiological or pathological inflammation. We designed two in vitro models that recapitulate the different phases of the reaction (recruitment, initiation, development, and resolution - \\"resolving model\\" - vs. persistence of inflammation \"persistent model): monocytes were exposed to different stimuli (microbial molecules, cytokines, and Immune complexes), and to sequential changes in microenvironmental conditions (temperature, hypoxia, amount of serum), at different time points (0, 4, 14, 24, 48 h for the resolving model and 0, 2, 4, 14, 24, 72, 96 h for the persistent model).
2020-06-30 | E-MTAB-8226 | biostudies-arrayexpress
Project description:Fibroblast activation is transient in successful wound repair, but persistent in fibrotic pathologies. Understanding fibroblast deactivation during successful wound healing may provide new approaches to therapeutically reverse fibrogenic cell activation. To characterize the gene programs that accompany fibroblast activation and reversal during lung fibrosis resolution, we used RNA-seq analysis of flow-sorted Col1α1-GFP positive and CD45, CD31, and CD326 negative cells isolated from the lungs of young mice exposed to bleomycin and pneumonectomy. We compared fibroblasts isolated from controls to those isolated at days 14 and 30 after bleomycin exposure, as well as at 14 days after pneumonectomy, representing the peak of extracellular matrix deposition, early stage of fibrosis resolution, and non-fibrotic lung repair respectively.
2020-11-13 | GSE161322 | GEO
Project description:Up to 30% of hospitalized COVID-19 patients experience persistent sequelae, including pulmonary fibrosis (PF). We examined COVID-19 survivors with impaired lung function and imaging worrisome for developing PF and found within six months, symptoms, restriction and PF improved in some (Early-Resolving COVID-PF), but persisted in others (Late-Resolving COVID-PF). To evaluate immune mechanisms associated with recovery versus persistent PF, we performed single-cell RNA-sequencing and multiplex immunostaining on peripheral blood mononuclear cells from patients with Early- and Late-Resolving COVID-PF and compared them to age-matched controls without respiratory disease. Our analysis showed circulating monocytes were significantly reduced in Late-Resolving COVID-PF patients compared to Early-Resolving COVID-PF and non-diseased controls. Monocyte abundance correlated with pulmonary function forced vital capacity and diffusion capacity. Differential expression analysis revealed MHC-II class molecules were upregulated on the CD8 T cells of Late-Resolving COVID-PF patients but downregulated in monocytes. To determine whether these immune signatures resembled other interstitial lung diseases, we analyzed samples from Idiopathic Pulmonary Fibrosis (IPF) patients. IPF patients had a similar marked decrease in monocyte HLA-DR protein expression compared to Late-Resolving COVID-PF patients. Our findings indicate decreased circulating monocytes is associates with decreased lung function and uniquely distinguishes Late-Resolving COVID-PF from Early-Resolving COVID-PF, IPF, and non-diseased controls.
2023-12-07 | GSE249513 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.
2020-11-18 | GSE161648 | GEO
Project description:These studies profiled the expression of mRNA in lung and spleen regulatory T cells in Foxp3EGFP mice during lipopolysaccharide-induced lung injury. Baseline, uninjured Lung Treg and Resolving Lung Tregs and Resolving Splenic Tregs were sorted (7 days after intratracheal instillation of LPS for Resolving conditions) and mRNAs differentially expressed (DE) between Control Lung Tregs, Resolving Lung Tregs and Resolving Splenic Tregs samples were identified using microarrays.
2019-02-12 | GSE104088 | GEO