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Lung injury-induced endothelial cell states persist in aging-associated non-resolving fibrosis II

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE264162 | GEO | 2024/06/04

REPOSITORIES: GEO

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Lung injury-induced endothelial cell states persist in aging-associated non-resolving fibrosis

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

Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

Project description:We identified the transcription factor ETS-related gene (ERG) as a putative orchestrator of lung capillary homeostasis and repair following injury, and whose function was dysregulated in aging. Single-cell RNA-seq of ERG deficient mouse lungs revealed transcriptional abnormalities and fibrogenic features, resembling those associated with aging and IPF, including reduced number of lung progenitor ECs, known as general capillary (gCap) ECs.

2021-12-31 | GSE187333 | GEO

mTert induction in p21-positive cells counteracts capillary rarefaction and pulmonary emphysema

Project description:Lung diseases develop when telomeres are shortened beyond a critical point. We have constructed a mouse model in which the catalytic subunit of telomerase (mTert), or its catalytically inactive form (mTertCI), is expressed from the p21Cdkn1a promoter. We found that this particular expression of mTert reduces senescence of endothelial cells (EC) in lungs of aged mice, as well as emphysema and pulmonary perivascular fibrosis. We also show that mTert counteracts the decline in capillary density in aged mice and promotes the maintenance of high numbers of Cd34+ cells, identified as a subclass of endothelial cells with proliferative capacity. In line with these results, young p21+/Tert mice treated with a VEGF receptor inhibitor combined with hypoxia are also protected against senescence and emphysema induced by this treatment. The catalytic activity of mTert is required for all the effects observed. However, and unexpectedly, we found that both mTert and mTertCI expression significantly reduced p21 levels in the lungs of aged mice. mTert thus protects against age-related and induced loss of capillary vessels and subsequent lung emphysema.

2023-06-29 | GSE165218 | GEO

Comparative transcriptional analysis of lung fibroblasts from young and aged mice identifies PIM1/NFATc1 axis as a driver of persistent fibrosis

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

Investigating the role of aging and lung fibrosis in Endothelial Cells with RNA sequencing

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). We found that lung fibrosis resolution in young mice was accompained by the activation of transcriptional programs promoting vascular repair and lung fibrosis resolution. Lung endothelial cells from aged mice after injury failed to activate these programs, leading to dysrepair and progressive fibrosis.

2021-09-30 | GSE181508 | GEO

A single cell transcriptome atlas of murine endothelial cells

Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.

2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress

Expression data from lung tissue of Zmpste24 defient or wildtype c57BL/6 mice

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

Thrombopoietin mimetic reduces mouse lung inflammation and fibrosis after radiation by attenuating activated endothelial phenotypes

Project description:Radiation-induced lung injury (RILI) initiates radiation pneumonitis and progresses to fibrosis as the main side effect of lung cancer patients treated with radiotherapy. There is no effective drug for RILI. Sustained vascular activation is a major contributor to the establishment of chronic disease. Here, using a whole thoracic irradiation (WTI) mouse model, we investigated the mechanisms and effectiveness of thrombopoietin mimetic (TPOm) for preventing RILI. We demonstrated that administering TPOm 24 hours before irradiation decreased histologic lung injury score, apoptosis, vascular permeability, expression of pro-inflammatory cytokines, and neutrophil infiltration in the lung of mice 2 weeks after WTI. We described the expression of c-MPL, a TPO receptor, in mouse primary pulmonary microvascular endothelial cells, showing TPOm reduced endothelial cell-neutrophil adhesion by inhibiting ICAM-1 expression. Seven months after WTI, TPOm-treated lung exhibited less collagen deposition, expression of MMP-9, TIMP-1, IL-6, TGF-b, and p21. Moreover, TPOm improved lung vascular structure, lung density, and respiration rate, leading to a prolonged survival time after WTI. Single-cell RNA sequencing analysis of lungs 2 weeks after WTI revealed that TPOm shifted populations of capillary endothelial cells towards a less activated and more homeostatic phenotype. Taken together, TPOm is protective for RILI by inhibiting endothelial cell activation.

2024-08-01 | GSE273235 | GEO

Brain endothelial cells are exquisite sensors of age-related circulatory cues

Project description:single cell RNAseq of brain endothelial cells in normal aging, aged and young plasma treatment, and LPS treatment

2020-03-05 | GSE146395 | GEO

Pathogenesis of influenza A(H7N9) virus in aged non-human primates

Project description:The avian influenza A(H7N9) virus has caused high mortality in humans, especially in the elderly; however, little is known about the mechanistic basis for this. In this study, we employed non-human primates to evaluate the effect of aging on the pathogenicity of A(H7N9) virus. We observed that A(H7N9) virus infection of aged animals (defined as 20–26 years) caused more severe symptoms than infection of young animals (defined as 2 3 years). In aged animals, lung inflammation was weak and virus infection was sustained. Although cytokine and chemokine expression in the lungs of most aged animals was lower than that in the lungs of young animals, one aged animal showed dysregulated proinflammatory cytokine and chemokine production, resulting in it being euthanized. These results suggest that attenuated or dysregulated immune responses in aged animals are responsible for the severe symptoms observed among elderly patients infected with A(H7N9) virus.

2020-06-13 | GSE152406 | GEO

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