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The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [CUT&RUN]

ABSTRACT: Smooth muscle-derived Sca1+ adventitial progenitor cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and matrix tissue. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the differentiation trajectory of AdvSca1-SM cells to myofibroblasts are unclear. Here we show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells in vivo after acute vascular injury and pharmacological inhibition of the Brg1 bromodomain by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness-related genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; Brg1 inhibition blocked TGF-β1-induced phenotypic transition. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal regulatory sequences of stemness-related genes and recruitment of Brg1 to promoters of myofibroblast-related genes. This recruitment of Brg1 to myofibroblast genes was blocked in the presence of PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit.

ORGANISM(S): Mus musculus

PROVIDER: GSE211422 | GEO | 2023/03/28

REPOSITORIES: GEO

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The chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and in situ vascular fibrosis [RNA-seq]

Project description:Smooth muscle-derived Sca1+ adventitial progenitor cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and matrix tissue. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the differentiation trajectory of AdvSca1-SM cells to myofibroblasts are unclear. Here we show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells in vivo after acute vascular injury and pharmacological inhibition of the Brg1 bromodomain by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness-related genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; Brg1 inhibition blocked TGF-β1-induced phenotypic transition. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal regulatory sequences of stemness-related genes and recruitment of Brg1 to promoters of myofibroblast-related genes. This recruitment of Brg1 to myofibroblast genes was blocked in the presence of PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit.

2023-03-28 | GSE211421 | GEO

Transcriptomic Changes in TGF-β1 Differentiated and PGE2 Dedifferentiated Myofibroblasts

Project description:These data show that the genes that distinguish myofibroblasts from fibroblasts are myriad, and that some genes not traditionally associated with myofibroblast differentiation may serve as novel therapeutic targets for fibrosing disorders. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. Here, we use transforming growth factor-β1 (TGF-β1) and prostaglandin E2 (PGE2), which has recently been shown to reverse myofibroblast differentiation, to investigate the transcriptomic changes that occur during TGF-β1-induced differentiation and PGE2-induced de-differentiation of myofibroblasts.

2015-06-30 | E-GEOD-63659 | biostudies-arrayexpress

Genome-wide transcript profiling for native porcine valvular interstitial cells and those cultured on TCPS and treated with TGF-β1

Project description:Fibrotic diseases have significant health impact and have been associated with differentiation of the resident fibroblasts into myofibroblasts. In particular, stiffened extracellular matrix and TGF-β1 in fibrotic lesions have been shown to promote pathogenic myofibroblast activation and progression of fibrosis in various tissues. To better understand the roles of mechanical and chemical cues on myofibroblast differentiation and how they may crosstalk, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves and studied how traditional TCPS culture, which presents a non-physiologically stiff environment, and TGF-β1 affect native VIC phenotypes. We carried out gene expression profiling using porcine genome microarrays from Affymetrix and found that traditional TCPS culture induces major changes in gene expression of native VICs, rendering these cells more activated and similar to cells treated with TGF-β1. We also monitored time-dependent effects induced by TGF-β1 by examining gene expression changes induced by TGF-β1 at 8 hours and 24 hours. Porcine aortic VICs were isolated and cultured with or without TGF-β1 treatment for RNA extraction and hybridization on Affymetrix microarrays. We included 3 biological replicates for each condition. P0 VICs were freshly isolated cells which had not been cultured. P2 VICs were cells that had been passaged 2 times and cultured on plastic plates in low serum media. Some of the P2 VICs were treated with TGF-β1 at 5ng/ml for 8 hours or 24 hours. All the control and TGF-β1-treated conditions were collected at the same time on day 3 of culture.

2013-09-02 | E-GEOD-48839 | biostudies-arrayexpress

Genome-wide transcript profiling for native porcine valvular interstitial cells and those cultured on TCPS and treated with TGF-β1

2013-09-02 | GSE48839 | GEO

Smooth muscle-derived progenitor cell myofibroblast differentiation through KLF4 downregulation promotes arterial remodeling and fibrosis

Project description:Resident vascular adventitial SCA1(+) progenitor (AdvSca1) cells are essential in vascular development and injury. However, the heterogeneity of AdvSca1 cells presents a unique challenge in understanding signaling pathways orchestrating their behavior in homeostasis and injury responses. Using smooth muscle cell (SMC) lineage tracing models, we identified a subpopulation of AdvSca1 cells (AdvSca1-SM) originating from mature SMCs that undergo reprogramming in situ and exhibit a multipotent phenotype. Here we employed lineage tracing and RNA sequencing to define the signaling pathways regulating SMC-to-AdvSca1-SM cell reprogramming and AdvSca1-SM progenitor cell phenotype. Unbiased hierarchical clustering revealed that genes related to hedgehog/WNT/beta-catenin signaling are significantly enriched in AdvSca1-SM cells, emphasizing the importance of this signaling axis in the reprogramming event. Leveraging AdvSca1-SM-specific expression of Gli1, we generated Gli1-CreERT2-ROSA26-YFP reporter mice to selectively track AdvSca1-SM cells. We demonstrated that physiologically relevant vascular injury or AdvSca1-SM cell-specific Klf4 depletion facilitated the proliferation and differentiation of AdvSca1-SM cells to a pro-fibrotic myofibroblast phenotype rather than macrophages. Surprisingly, AdvSca1-SM cells selectively contributed to adventitial remodeling and fibrosis, but little to neointima formation. Together, these findings strongly support therapeutics aimed at preserving the AdvSca1-SM cell phenotype as a viable anti-fibrotic approach.

2020-02-20 | GSE145569 | GEO

Transcription profiling of human IMR-90 cells in response to TGF-I?1

Project description:Members of the NADPH oxidase (NOX) family of enzymes, which catalyze the reduction of O2 to reactive oxygen species, have increased in number during eukaryotic evolution. Seven isoforms of the NOX gene family have been identified in mammals; however, specific roles of NOX enzymes in mammalian physiology and pathophysiology have not been fully elucidated. The best established physiological role of NOX enzymes is in host defense against pathogen invasion in diverse species, including plants. The prototypical member of this family, NOX-2 (gp91phox), is expressed in phagocytic cells and mediates microbicidal activities. Here we report a role for the NOX4 isoform in tissue repair functions of myofibroblasts and fibrogenesis. Transforming growth factor-β1 (TGF-β1) induces NOX-4 expression in lung mesenchymal cells by a SMAD-3–dependent mechanism. NOX-4–dependent generation of hydrogen peroxide (H2O2) is required for TGF-β1–induced myofibroblast differentiation, extracellular matrix (ECM) production and contractility. NOX-4 is upregulated in lungs of mice subjected to noninfectious injury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic or pharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models of lung injury. These studies support a function for NOX4 in tissue fibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 in recalcitrant fibrotic disorders. Experiment Overall Design: mRNA expression of genes in human fetal lung mesenchymal cells (IMR-90) treated with or without TGF-β1, as analyzed by Affymetrix (U133A) microarrays. Control (C0, C2, C3) = cells without TGF-β1 treatment (n=3). Experimental (T0, T5, T7) = cells treated with TGF-β1 (2ng/ml) (n=3). mRNA was collected for all 6 samples for 48 hours post treatment.

2009-08-25 | E-GEOD-17518 | biostudies-arrayexpress

Smooth muscle-derived adventitial progenitor cells direct atherosclerotic plaque composition complexity in a Klf4-dependent manner

Project description:We previously established that vascular smooth muscle-derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM cell lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM-derived cells localized throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMCs), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared to WT mice. Additionally, Klf4 deletion drastically modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMCs and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potential unstable atherosclerotic plaques.

2024-01-03 | GSE244439 | GEO

Role of ZNF281 in intestinal fibroblast activation: new insights in IBD-related fibrosis

Project description:Serious complications of Crohn’s disease (CD), a form of Inflammatory Bowel Disease (IBD), involve the formation of intestinal fibrotic stenosis followed by obstruction. Chronic inflammatory state activates resident fibroblasts and myofibroblasts, that are the key effector cells in fibrosis, being responsible for the synthesis of ECM proteins. Exposure of human colon fibroblasts (CCD18-Co) to the pro-fibrotic cytokine TGF-β1 is sufficient to induce the expression of genes associated with myofibroblast features such as cell migration, ECM remodeling and contraction. Furthermore, during TGFβ1-mediated myofibroblast differentiation, the transcription factor ZNF281 is increased and is required to reshape the expression of genes encoding for myofibroblast markers, suggesting an active role for ZNF281 as a master regulator of intestinal myofibroblast functions.

2022-09-02 | GSE204868 | GEO

Human Tendon-on-a-Chip for modeling vascular inflammatory fibrosis II

Project description:Vascular inflammation and myofibroblast activation by TGF-β1 are key, yet-to-be-fully-understood pathological processes in fibrosis. Here we report the development of a novel human Tendon-on-a-Chip (hToC) to elucidate the role of TGF-β1 in peritendinous adhesions, a debilitating fibrosis condition affecting flexor tendon, which currently lacks biological therapies. The hToC allows the crosstalk between a vascular compartment harboring endothelial cells and monocytes with a tissue hydrogel compartment containing tendon fibroblasts and macrophages. We find that the hToC replicates in vivo inflammatory and fibrotic phenotypes in preclinical and clinical samples, including myofibroblast differentiation and tissue contraction, excessive ECM deposition, and inflammatory cytokines secretion. We further show the fibrotic phenotypes are driven by the interactions between the vascular and tissue compartments, mediating the transmigration of monocytes. We demonstrate significant overlap in fibrotic transcriptional signatures in the hToC with human tenolysis samples, including the mTOR pathway, a regulatory nexus of fibrosis across various organs. Treatment with Rapamycin suppressed the fibrotic phenotype on the hToC, which validates the hToC as a preclinical alternative for investigating fibrosis and testing therapeutics.

2024-01-10 | GSE246391 | GEO

Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer [single-cell RNA-seq]

Project description:Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumour progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. This identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-β1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-β1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo phenotypes. Similarly, IL-1β treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signalling identified additional pathways and cell interactions likely to be involved in fibroblast activation, This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC.

2020-07-08 | GSE153935 | GEO

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