Evidence for a lipofibroblast-to-Cthrc1pos myofibroblast reversible switch during the development and resolution of lung fibrosis in old mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253453 | GEO | 2025/05/05
REPOSITORIES: GEO
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Similar Datasets
Project description:Question addressed in the study: Genetic lineage tracing of alpha smooth muscle actin-positive (ACTA2+) cells in the context of bleomycin-induced pulmonary fibrosis in mice has shown that activated myofibroblasts (aMYFs) differentiate into lipofibroblasts (LIFs) during fibrosis resolution. However, the heterogeneity of the different mesenchymal cell subclusters during fibrosis formation and their contribution to the aMYFs as well as the fate of aMYFs during fibrosis resolution are still unclear. Materials and methods: Two-month-old Tg(Acta2-CreERT2); tdTomatoflox mice were used to label Acta2pos cells before (Tam-Bleo condition) or after (Bleo-Tam condition) bleomycin administration. Using scRNA-seq, the origin and fate of Acta2pos cells converging on the aMYF/Cthrc1pos myofibroblast lineage, were analyzed at the peak of fibrosis formation (day 14) as well as during resolution (day 60). Mining of human IPF scRNA-seq data was also carried out. The function of resident mesenchymal cells derived from saline or bleomycin-injured lungs during fibrosis formation or resolution in supporting AT2 progenitor cell renewal was assessed using alveolar organoid assays. Results: By employing the dimensionality reduction and UMAP visualization MYF/Cthrc1pos cells were identified and characterized in three scRNA-seq conditions: Saline, Tam-Bleo and Bleo-Tam. Acta2pos cells isolated from saline-treated mice revealed the presence of Acta2pos cells in the expected airway and vascular smooth muscle cells, but also in alveolar fibroblasts, peribronchial and adventitial fibroblasts as well as in a restricted number of Cthrc1pos cells indicating a primed pro-fibrotic status of the non-injured lung. In Tam-Bleo lungs, minimal contribution of these cells to the Cthrc1pos pool was observed. By contrast, labeling of Acta2pos cells following bleo administration (Bleo-Tam) led to massive labeling of Cthrc1pos cells, which following fine clustering were grouped into 4 subclusters named F1-F4. Interestingly, cells in cluster F1 were identified as Cthrc1low and displayed a strong LIF signature (LIFhigh) while cells in cluster F2 were LIFlow and Cthrc1high. Examination of F1 and F2 subclusters during fibrosis resolution suggested that F2 transition back to an F1 status and eventually differentiate into Cthrc1low LIFhigh alveolar fibroblasts. Analysis of the alveolar fibroblast cluster revealed the presence of three subclusters (A, B and C). Cluster C appeared only in Bleo-Tam and displayed a fibrotic signature (Sfrp1, Eln, Ltbp2, Spp1high). These cells, which originate from Acta2neg alveolar fibroblasts are suggested to differentiate into the Cthrc1low LIFhigh F1 subcluster. Data mining of human scRNA-seq from fibrotic lungs supported the conservation of the heterogeneity of the CTHRC1pos population. Alveolosphere assays indicated that resident mesenchymal cells did not reacquire their stem cell niche function at day 60, during fibrosis resolution. Answer to the question: Our results support a LIF-to-aMYF reversible switch during fibrosis formation and resolution.
2024-12-31 | GSE223664 | GEO
Project description:Question addressed in the study: Genetic lineage tracing of alpha smooth muscle actin-positive (ACTA2+) cells in the context of bleomycin-induced pulmonary fibrosis in mice has shown that activated myofibroblasts (aMYFs) differentiate into lipofibroblasts (LIFs) during fibrosis resolution. However, the heterogeneity of the different mesenchymal cell subclusters during fibrosis formation and their contribution to the aMYFs as well as the fate of aMYFs during fibrosis resolution are still unclear. Materials and methods: Two-month-old Tg(Acta2-CreERT2); tdTomatoflox mice were used to label Acta2pos cells before (Tam-Bleo condition) or after (Bleo-Tam condition) bleomycin administration. Using scRNA-seq, the origin and fate of Acta2pos cells converging on the aMYF/Cthrc1pos myofibroblast lineage, were analyzed at the peak of fibrosis formation (day 14) as well as during resolution (day 60). Mining of human IPF scRNA-seq data was also carried out. The function of resident mesenchymal cells derived from saline or bleomycin-injured lungs during fibrosis formation or resolution in supporting AT2 progenitor cell renewal was assessed using alveolar organoid assays. Results: By employing the dimensionality reduction and UMAP visualization MYF/Cthrc1pos cells were identified and characterized in three scRNA-seq conditions: Saline, Tam-Bleo and Bleo-Tam. Acta2pos cells isolated from saline-treated mice revealed the presence of Acta2pos cells in the expected airway and vascular smooth muscle cells, but also in alveolar fibroblasts, peribronchial and adventitial fibroblasts as well as in a restricted number of Cthrc1pos cells indicating a primed pro-fibrotic status of the non-injured lung. In Tam-Bleo lungs, minimal contribution of these cells to the Cthrc1pos pool was observed. By contrast, labeling of Acta2pos cells following bleo administration (Bleo-Tam) led to massive labeling of Cthrc1pos cells, which following fine clustering were grouped into 4 subclusters named F1-F4. Interestingly, cells in cluster F1 were identified as Cthrc1low and displayed a strong LIF signature (LIFhigh) while cells in cluster F2 were LIFlow and Cthrc1high. Examination of F1 and F2 subclusters during fibrosis resolution suggested that F2 transition back to an F1 status and eventually differentiate into Cthrc1low LIFhigh alveolar fibroblasts. Analysis of the alveolar fibroblast cluster revealed the presence of three subclusters (A, B and C). Cluster C appeared only in Bleo-Tam and displayed a fibrotic signature (Sfrp1, Eln, Ltbp2, Spp1high). These cells, which originate from Acta2neg alveolar fibroblasts are suggested to differentiate into the Cthrc1low LIFhigh F1 subcluster. Data mining of human scRNA-seq from fibrotic lungs supported the conservation of the heterogeneity of the CTHRC1pos population. Alveolosphere assays indicated that resident mesenchymal cells did not reacquire their stem cell niche function at day 60, during fibrosis resolution. Answer to the question: Our results support a LIF-to-aMYF reversible switch during fibrosis formation and resolution.
2025-02-12 | GSE221402 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease where invasive pulmonary myofibroblasts secrete collagen and destroy lung integrity. Here we show that IL-11 is upregulated in the lung of IPF patients, associated with disease severity and is secreted from IPF fibroblasts. In vitro, IL-11 stimulates lung fibroblasts to become invasive, ACTA2+ve, collagen secreting myofibroblasts, in an ERK-dependent fashion. In mice, fibroblast-specific transgenic expression or administration of Il-11 drives lung fibroblast-to-myofibroblast transformation and causes lung fibrosis. Il11ra1 deleted mice, whose lung fibroblasts are unresponsive to pro-fibrotic stimulation, are protected from fibrosis in the bleomycin mouse model of pulmonary fibrosis. We generated an IL-11 neutralising antibody that blocks lung fibroblast activation downstream of multiple stimuli and reverses myofibroblast activation. In therapeutic studies, anti-IL-11 treatment both prevented and reversed lung fibrosis, which was accompanied by diminished Erk activation. These data prioritise IL-11 as a drug target for lung fibrosis and IPF.
2022-05-06 | GSE130983 | 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:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Experiment Overall Design: We isolated two myofibroblast cell culture from patients with idiopathic pulmonary fibrosis. Embryonic pulmonary fibroblast was used for the reference.
2008-06-15 | E-GEOD-6804 | biostudies-arrayexpress
Project description:Background: Myofibroblasts (MYFs) are generally considered the principal culprits in excessive extracellular matrix deposition and scar formation in the pathogenesis of lung fibrosis. Lipofibroblasts (LIFs), on the other hand, are defined by their lipid-storing capacity and are predominantly found in the alveolar regions of the lung. They have been proposed to play a protective role in lung fibrosis. We previously reported that a LIF to MYF reversible differentiation switch occurred during fibrosis formation and resolution. In this study, we tested whether WI-38 cells, a human embryonic lung fibroblast cell line, could be used to study fibroblast differentiation towards the LIF or MYF phenotype and whether this could be relevant for idiopathic pulmonary fibrosis (IPF). Methods: using WI-38 cells, MYF differentiation was triggered using TGF-β1 treatment and LIF differentiation using Metformin treatment. We analyzed the LIF to MYF and MYF to LIF differentiation by pre-treating the WI-38 cells with TGF-β1 or Metformin first, followed by treatment with Metformin and TGF-β1, respectively. We used IF, qPCR and bulk RNA-Seq to analyze the phenotypic and transcriptomic changes in the cells. We correlated our in vitro transcriptome data from WI-38 cells (obtained via bulk RNA sequencing) with the transcriptomic signature of LIFs and MYFs derived from the IPF cell atlas as well as with our own single-cell transcriptomic data from IFP patients-derived lung fibroblasts (LF-IPF) cultured in vitro. We also carried out alveolosphere assays to evaluate the ability of the proposed LIF and MYF cells to support the growth of alveolar epithelial type 2 cells. Results: WI-38 and LF-IPF display similar phenotypical and gene expression responses to TGF-β1 and Metformin treatment. Bulk RNA-Seq analysis of WI-38 and LF-IPF treated with TGF-β1, or Metformin indicate similar transcriptomic changes. We also show the partial conservation of the LIF and MYF signature extracted from the Habermann et al. scRNA-seq dataset in WI-38 cells treated with Metformin or TGF-β1, respectively. Alveolosphere assays indicate that LIFs enhance organoid growth, while MYFs inhibit organoid growth. Finally, we provide evidence supporting the LIF to MYF reversible switch using WI-38 cells. Conclusions: WI-38 cells represent a versatile and reliable model to study the intricate dynamics of fibroblast differentiation towards the MYF or LIF phenotype associated with lung fibrosis formation and resolution, providing valuable insights to drive future research
2024-07-03 | GSE264038 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal pulmonary disorder characterized by fibroblast proliferation and the excess deposit of extracellular matrix proteins. The etiology of IPF is unknown, but a central role for microRNAs (miRNAs), a class of small non-coding regulatory RNAs, has been recently suggested. We report the upregulation of miR-199a-5p in mouse lungs undergoing bleomycin-induced fibrosis and also in human biopsies from IPF patients. Levels of miR-199a-5p were increased selectively in myofibroblasts and putative profibrotic effects of miR-199a-5p were further investigated in cultured lung fibroblasts. MiR-199a-5p expression was induced upon TGFβ exposure and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts. CAV1, a critical mediator of pulmonary fibrosis, was established as a bona fide target of miR-199a-5p. Finally, we also found an aberrant expression of miR-199a-5p in mouse models of kidney and liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. We propose miR-199a-5p as a major regulator of fibrosis that represents a potential therapeutic target to treat fibroproliferative diseases. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-02-01 | E-GEOD-34818 | biostudies-arrayexpress
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group
2014-10-28 | E-GEOD-48455 | biostudies-arrayexpress
Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA
2008-11-20 | E-GEOD-11196 | biostudies-arrayexpress
Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
2023-02-06 | PXD029625 | Pride